Editing Peripheral membrane protein

{{Short description|Membrane proteins that adhere temporarily to membranes with which they are associated}}
'''Peripheral membrane proteins''', or '''extrinsic membrane proteins''',<ref>{{Cite web |title=extrinsic protein {{!}} biology {{!}} Britannica |url=https://www.britannica.com/science/extrinsic-protein |access-date=2022-07-04 |website=www.britannica.com |language=en}}</ref> are [[membrane protein]]s that adhere only temporarily to the [[biological membrane]] with which they are associated. These [[protein]]s attach to [[integral membrane protein]]s, or penetrate the peripheral regions of the [[lipid bilayer]]. The regulatory protein subunits of many [[ion channel]]s and [[transmembrane receptor]]s, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a [[protein purification]] procedure. Proteins with [[GPI anchor]]s are an exception to this rule and can have purification properties similar to those of integral membrane proteins.

The reversible attachment of proteins to biological membranes has shown to regulate [[cell signaling]] and many other important cellular events, through a variety of mechanisms.<ref name="Cafiso1">{{cite book| vauthors = Cafiso DS |author-link=David S. Cafiso |chapter=Structure and interactions of [[C2 domain]]s at membrane surfaces | veditors = Tamm LK |title=Protein-Lipid Interactions: From Membrane Domains to Cellular Networks| url=https://books.google.com/books?visbn=3527311513 | pages=403–22 |publisher=John Wiley & Sons |location=Chichester |year= 2005 |isbn=3-527-31151-3}}</ref> For example, the close association between many [[enzyme]]s and biological membranes may bring them into close proximity with their lipid [[Substrate (biochemistry)|substrate]](s).<ref name="Ghosh">{{cite journal | vauthors = Ghosh M, Tucker DE, Burchett SA, Leslie CC | title = Properties of the Group IV phospholipase A2 family | journal = Progress in Lipid Research | volume = 45 | issue = 6 | pages = 487–510 | date = November 2006 | pmid = 16814865 | doi = 10.1016/j.plipres.2006.05.003 | name-list-style = vanc }}</ref> '''Membrane binding''' may also promote rearrangement, dissociation, or [[conformational change]]s within many protein structural domains, resulting in an activation <!-- or de-activation? any evidence for this? --> of their [[biological activity]].<ref name="Johnson_2002"/><ref name="Guruvasuthevan">{{cite journal | vauthors = Thuduppathy GR, Craig JW, Kholodenko V, Schon A, Hill RB | title = Evidence that membrane insertion of the cytosolic domain of Bcl-xL is governed by an electrostatic mechanism | journal = Journal of Molecular Biology | volume = 359 | issue = 4 | pages = 1045–1058 | date = June 2006 | pmid = 16650855 | pmc = 1785297 | doi = 10.1016/j.jmb.2006.03.052 }}</ref> Additionally, the positioning of many proteins are localized to either the inner or outer surfaces or leaflets of their resident membrane.<ref name="Takida">{{cite journal | vauthors = Takida S, Wedegaertner PB | title = Exocytic pathway-independent plasma membrane targeting of heterotrimeric G proteins | journal = FEBS Letters | volume = 567 | issue = 2–3 | pages = 209–213 | date = June 2004 | pmid = 15178324 | doi = 10.1016/j.febslet.2004.04.062 | s2cid = 36940600 | doi-access = free | bibcode = 2004FEBSL.567..209T }}</ref>
This facilitates the assembly of multi-protein complexes by increasing the probability of any appropriate [[protein–protein interactions]].

[[Image:Monotopic membrane protein.svg|thumb|right|400px|Schematic representation of the different types of interaction between monotopic membrane proteins and the [[cell membrane]]:
1. interaction by an amphipathic [[α-helix]] parallel to the membrane plane (in-plane membrane helix)
2. interaction by a hydrophobic loop
3. interaction by a covalently bound membrane lipid (''lipidation'')
4. electrostatic or [[Intermolecular forces#Ionic interactions|ionic interactions]] with membrane lipids (''e.g.'' through a calcium ion)]]

==Binding to the lipid bilayer==
[[Image:1mai.png|thumb|right|250px| PH domain of phospholipase C delta 1. Middle plane of the lipid bilayer – black dots. Boundary of the hydrocarbon core region – blue dots (intracellular side). Layer of lipid phosphates – yellow dots.]]
Peripheral membrane proteins may interact with other proteins or directly with the [[lipid bilayer]]. In the latter case, they are then known as ''amphitropic'' proteins.<ref name="Johnson_2002">{{cite journal | vauthors = Johnson JE, Cornell RB | title = Amphitropic proteins: regulation by reversible membrane interactions (review) | journal = Molecular Membrane Biology | volume = 16 | issue = 3 | pages = 217–235 | year = 2002 | pmid = 10503244 | doi = 10.1080/096876899294544 | doi-access = free }}</ref>
Some proteins, such as [[G-protein]]s and certain [[protein kinase]]s, interact with [[transmembrane protein]]s and the lipid bilayer simultaneously. Some polypeptide [[hormones]], [[antimicrobial peptides]], and [[neurotoxins]] accumulate at the membrane surface prior to locating and interacting with their cell surface receptor targets, which may themselves be peripheral membrane proteins. <!-- I think? -->

The [[phospholipid bilayer]] that forms the cell surface membrane consists of a [[hydrophobic]] inner core region sandwiched between two regions of [[hydrophilic]]ity, one at the inner surface and one at the outer surface of the cell membrane (see [[lipid bilayer#Structure and organization|lipid bilayer]] article for a more detailed structural description of the cell membrane). The inner and outer surfaces, or interfacial regions, of model [[phospholipid]] bilayers have been shown to have a thickness of around 8 to 10 [[Ångström|Å]], although this may be wider in [[biological membrane]]s that include large amounts of [[ganglioside]]s or [[lipopolysaccharide]]s.<ref name="McInosh">{{cite book| vauthors = McIntosh TJ, Vidal A, Simon SA |chapter=The energetics of peptide-lipid interactions: modification by interfacial dipoles and cholesterol |title=Current Topics in Membranes |volume=52 |pages=205–253 |publisher=Academic Press |year=2003 |isbn=978-0-12-643871-0}}</ref>
The hydrophobic inner core region of typical [[biological membranes]] may have a thickness of around 27 to 32 Å, as estimated by [[Small angle X-ray scattering (SAXS)]].<ref name="Mitra">{{cite journal | vauthors = Mitra K, Ubarretxena-Belandia I, Taguchi T, Warren G, Engelman DM | title = Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 12 | pages = 4083–4088 | date = March 2004 | pmid = 15016920 | pmc = 384699 | doi = 10.1073/pnas.0307332101 | doi-access = free | bibcode = 2004PNAS..101.4083M }}</ref>
The boundary region between the hydrophobic inner core and the hydrophilic interfacial regions is very narrow, at around 3 Å, (see [[lipid bilayer#Structure and organization|lipid bilayer]] article for a description of its component chemical groups). Moving outwards away from the hydrophobic core region and into the interfacial hydrophilic region, the effective concentration of water rapidly changes across this boundary layer, from nearly zero to a concentration of around 2 [[Concentration#Molality|M]].<ref name=Marsh_2001>{{cite journal | vauthors = Marsh D | title = Polarity and permeation profiles in lipid membranes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 14 | pages = 7777–7782 | date = July 2001 | pmid = 11438731 | pmc = 35418 | doi = 10.1073/pnas.131023798 | doi-access = free | bibcode = 2001PNAS...98.7777M }}</ref><ref name=Marsh_2002>{{cite journal | vauthors = Marsh D | title = Membrane water-penetration profiles from spin labels | journal = European Biophysics Journal | volume = 31 | issue = 7 | pages = 559–562 | date = December 2002 | pmid = 12602343 | doi = 10.1007/s00249-002-0245-z | s2cid = 36212541 }}</ref>
The phosphate groups within phospholipid bilayers are fully hydrated or saturated with water and are situated around 5 Å outside the boundary of the hydrophobic core region.<ref name=Nagle_2000>{{cite journal | vauthors = Nagle JF, Tristram-Nagle S | title = Structure of lipid bilayers | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes | volume = 1469 | issue = 3 | pages = 159–195 | date = November 2000 | pmid = 11063882 | pmc = 2747654 | doi = 10.1016/S0304-4157(00)00016-2 }}</ref>

Some water-soluble proteins associate with lipid bilayers ''irreversibly'' and can form transmembrane alpha-helical or [[beta-barrel]] channels. Such transformations occur in [[pore forming toxins]] such as [[colicin]] A, alpha-hemolysin, and others. They may also occur in [[Bcl-2-associated X protein|BcL-2 like protein]] <!-- reference? -->, in some amphiphilic [[antimicrobial peptides]] <!-- reference? -->, and in certain [[annexin]]s <!-- reference? -->. These proteins are usually described as peripheral as one of their conformational states is water-soluble or only loosely associated with a membrane.<ref name="Goñi_2002">{{cite journal | vauthors = Goñi FM | title = Non-permanent proteins in membranes: when proteins come as visitors (Review) | journal = Molecular Membrane Biology | volume = 19 | issue = 4 | pages = 237–245 | year = 2002 | pmid = 12512770 | doi = 10.1080/0968768021000035078 | s2cid = 20892603 }}</ref>

==Membrane binding mechanisms==
[[Image:1poc.png|thumb|right|250px| Bee venom [[phospholipase A2]] (1poc). Middle plane of the lipid bilayer – black dots. Boundary of the hydrocarbon core region – red dots (extracellular side). Layer of lipid phosphates – yellow dots. ]]
The association of a protein with a [[lipid bilayer]] may involve significant changes within [[tertiary structure]] of a protein. These may include the [[protein folding|folding]] of regions of protein structure that were previously unfolded <!-- reference --> or a re-arrangement in the folding or a refolding of the membrane-associated part of the proteins. It also may involve the formation or dissociation of protein [[quaternary structure]]s or [[Oligomer|oligomeric complexes]], and specific binding of [[ion]]s, [[Ligand (biochemistry)|ligands]], or [[Phosphatidylinositol|regulatory lipids]]. <!-- reference -->

Typical amphitropic proteins must interact strongly with the lipid bilayer in order to perform their biological functions. <!-- reference --> These include the enzymatic processing of lipids and other hydrophobic substances, membrane anchoring, and the binding and transfer of small nonpolar compounds between different cellular membranes.<!--references for all these functions ? --> These proteins may be anchored to the bilayer as a result of hydrophobic interactions between the bilayer and exposed nonpolar residues at the surface of a protein,<ref>{{cite journal | vauthors = Goforth RL, Chi AK, Greathouse DV, Providence LL, Koeppe RE, Andersen OS | title = Hydrophobic coupling of lipid bilayer energetics to channel function | journal = The Journal of General Physiology | volume = 121 | issue = 5 | pages = 477–493 | date = May 2003 | pmid = 12719487 | pmc = 2217378 | doi = 10.1085/jgp.200308797 }}</ref> by specific non-covalent binding interactions with regulatory lipids <!-- ref -->, or through their attachment to [[Lipid anchored protein|covalently bound lipid anchors]]. <!-- ref, this whole paragraph, could do with more references ! -->

It has been shown that the membrane binding affinities of many peripheral proteins depend on the specific lipid composition of the membrane with which they are associated.<ref name="McIntosh">{{cite journal | vauthors = McIntosh TJ, Simon SA | title = Roles of bilayer material properties in function and distribution of membrane proteins | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 35 | issue = 1 | pages = 177–198 | year = 2006 | pmid = 16689633 | doi = 10.1146/annurev.biophys.35.040405.102022 }}</ref>
[[File:Proteïna amfitròpica.png|thumb|amphitropic proteins bind to hydrophobic anchor structures]]

===Non-specific hydrophobic association===
Amphitropic proteins associate with lipid bilayers via various [[hydrophobic]] anchor structures. Such as [[amphiphilic]] [[α-helix]]es, exposed nonpolar loops, post-translationally acylated or lipidated amino acid residues, or acyl chains of specifically bound regulatory lipids such as [[Phosphatidylinositol|phosphatidylinositol phosphate]]s. Hydrophobic interactions have been shown to be important even for highly cationic peptides and proteins, such as the polybasic domain of the [[MARCKS protein]] or histactophilin, when their natural hydrophobic anchors are present. <!-- what does this last bit mean, are hydrophobic interactions not important when they have a none natural anchor, if so why ! --><ref name="Hanakam_1996"/>

===Covalently bound lipid anchors===
[[Lipid anchored protein]]s are covalently attached to different [[fatty acid]] [[acyl]] chains on the [[cytoplasm]]ic side of the [[cell membrane]] via [[palmitoylation]], [[myristoylation]], or [[prenylation]]. On the exoplasmic face of the cell membrane, lipid anchored proteins are covalently attached to the [[lipids]] [[glycosylphosphatidylinositol]] (GPI) and [[cholesterol]].<ref name="Silvius">{{cite book| vauthors = Silvius JR |chapter=Lipidated peptides as tools for understanding the membrane interactions of lipid-modified proteins |title=Current Topics in Membranes |volume=52 |pages=371–395 |publisher=Academic Press |year=2003 |isbn=978-0-12-643871-0}}</ref><ref name="Baumann">{{cite book| vauthors = Baumann NA, Mennon AK |chapter=Lipid modifications of proteins | veditors = Vance DE, Vance JE |title=Biochemistry of Lipids, Lipoproteins and Membranes |pages=37–54 |edition=4th |publisher=Elsevier Science |year=2002 |isbn=978-0-444-51139-3}}</ref> Protein association with membranes through the use of [[acyl]]ated residues is a [[reversible process (thermodynamics)|reversible process]], as the acyl chain can be buried in a protein's hydrophobic binding pocket after dissociation from the membrane. This process occurs within the beta-subunits of [[G-protein]]s<!-- ref -->. Perhaps because of this additional need for structural flexibility, lipid anchors are usually bound to the highly flexible segments of proteins tertiary structure that are not well resolved by [[protein crystallography|protein crystallographic studies]].

===Specific protein–lipid binding===
[[Image:1h6h.png|thumb|right|250px| P40phox PX domain of NADPH oxidase Middle plane of the lipid bilayer – black dots. Boundary of the hydrocarbon core region – blue dots (intracellular side). Layer of lipid phosphates – yellow dots.]]
Some [[cytosolic]] proteins are recruited to different cellular membranes by recognizing certain types of lipid found within a given membrane.<ref name="Cho">{{cite journal | vauthors = Cho W, Stahelin RV | title = Membrane-protein interactions in cell signaling and membrane trafficking | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 34 | pages = 119–151 | date = June 2005 | pmid = 15869386 | doi = 10.1146/annurev.biophys.33.110502.133337 | name-list-style = amp }}</ref> Binding of a protein to a specific lipid occurs via specific membrane-targeting structural domains that occur within the protein and have specific binding pockets for the [[phospholipids#Amphipathic character|lipid head groups]] of the lipids to which they bind. This is a typical [[biochemistry|biochemical]] protein–[[Ligand (biochemistry)|ligand]] interaction, and is stabilized by the formation of intermolecular [[hydrogen bond]]s, [[van der Waals force|van der Waals interactions]], and [[hydrophobic|hydrophobic interactions]] between the protein and lipid [[ligand]]. Such complexes are also stabilized by the formation of ionic bridges between the [[aspartate]] or [[glutamate]] residues of the protein and lipid phosphates via intervening [[calcium]] ions (Ca<sup>2+</sup>).<!-- ref --> Such ionic bridges can occur and are stable when ions (such as Ca<sup>2+</sup>) are already bound to a protein in solution, prior to lipid binding. The formation of ionic bridges is seen in the protein–lipid interaction between both protein [[C2 domain|C2 type domains]] and [[annexin]]s.<!-- ref -->.

===Protein–lipid electrostatic interactions===
Any positively charged protein will be attracted to a negatively charged membrane by nonspecific [[electrostatic]] interactions. However, not all peripheral peptides and proteins are cationic, and only certain sides of [[biological membranes|membrane]] are negatively charged. These include the cytoplasmic side of [[Cell membrane|plasma membrane]]s, the outer leaflet of [[bacterial outer membrane]]s and [[mitochondria]]l membranes. Therefore, [[electrostatic|electrostatic interactions]] play an important role in [[Protein targeting|membrane targeting]] of [[electron]] carriers such as [[cytochrome c]], cationic toxins such as [[charybdotoxin]], and specific membrane-targeting domains such as some [[PH domain]]s, [[C1 domain]]s, and [[C2 domain]]s.

Electrostatic interactions are strongly dependent on the [[ionic strength]] of the solution. These interactions are relatively weak at the physiological ionic strength ([[Molar solution|0.14M NaCl]]): ~3 to 4 kcal/mol for small cationic proteins, such as [[cytochrome c]], [[charybdotoxin]] or [[hisactophilin]].<ref name="Hanakam_1996">{{cite journal | vauthors = Hanakam F, Gerisch G, Lotz S, Alt T, Seelig A | title = Binding of hisactophilin I and II to lipid membranes is controlled by a pH-dependent myristoyl-histidine switch | journal = Biochemistry | volume = 35 | issue = 34 | pages = 11036–11044 | date = August 1996 | pmid = 8780505 | doi = 10.1021/bi960789j }}</ref><ref name="Ben-Tal">{{cite journal | vauthors = Ben-Tal N, Honig B, Miller C, McLaughlin S | title = Electrostatic binding of proteins to membranes. Theoretical predictions and experimental results with charybdotoxin and phospholipid vesicles | journal = Biophysical Journal | volume = 73 | issue = 4 | pages = 1717–1727 | date = October 1997 | pmid = 9336168 | pmc = 1181073 | doi = 10.1016/S0006-3495(97)78203-1 | bibcode = 1997BpJ....73.1717B }}</ref><ref name="Sankaram_1993">{{cite book| vauthors = Sankaram MB, Marsh D |chapter=Protein-lipid interactions with peripheral membrane proteins |title=Protein-lipid interactions | veditors = Watts A |pages=127–162 |publisher=Elsevier |year=1993 |isbn=0-444-81575-9}}</ref>

==Spatial position in membrane==
Orientations and penetration depths of many amphitropic proteins and peptides in membranes are studied using [[site-directed spin labeling]],<ref name="Malmberg">{{cite journal | vauthors = Malmberg NJ, Falke JJ | title = Use of EPR power saturation to analyze the membrane-docking geometries of peripheral proteins: applications to C2 domains | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 34 | issue = 1 | pages = 71–90 | year = 2005 | pmid = 15869384 | pmc = 3637887 | doi = 10.1146/annurev.biophys.34.040204.144534 }}</ref> chemical labeling, measurement of membrane binding affinities of protein [[mutagenesis|mutants]],<ref name="Spencer">{{cite journal | vauthors = Spencer AG, Thuresson E, Otto JC, Song I, Smith T, DeWitt DL, Garavito RM, Smith WL | display-authors = 6 | title = The membrane binding domains of prostaglandin endoperoxide H synthases 1 and 2. Peptide mapping and mutational analysis | journal = The Journal of Biological Chemistry | volume = 274 | issue = 46 | pages = 32936–32942 | date = November 1999 | pmid = 10551860 | doi = 10.1074/jbc.274.46.32936 | doi-access = free }}</ref> [[fluorescence]] spectroscopy,<ref name="Lathrop">{{cite journal | vauthors = Lathrop B, Gadd M, Biltonen RL, Rule GS | title = Changes in Ca2+ affinity upon activation of Agkistrodon piscivorus piscivorus phospholipase A2 | journal = Biochemistry | volume = 40 | issue = 11 | pages = 3264–3272 | date = March 2001 | pmid = 11258945 | doi = 10.1021/bi001901n }}</ref> solution or solid-state [[NMR spectroscopy]],<ref name="Kuta">{{cite journal | vauthors = Kutateladze T, Overduin M | title = Structural mechanism of endosome docking by the FYVE domain | journal = Science | volume = 291 | issue = 5509 | pages = 1793–1796 | date = March 2001 | pmid = 11230696 | doi = 10.1126/science.291.5509.1793 | bibcode = 2001Sci...291.1793K }}</ref>
ATR [[Fourier transform spectroscopy|FTIR spectroscopy]],<ref name="Tatulian">{{cite journal | vauthors = Tatulian SA, Qin S, Pande AH, He X | title = Positioning membrane proteins by novel protein engineering and biophysical approaches | journal = Journal of Molecular Biology | volume = 351 | issue = 5 | pages = 939–947 | date = September 2005 | pmid = 16055150 | doi = 10.1016/j.jmb.2005.06.080 | url = https://zenodo.org/record/894918 }}</ref> X-ray or neutron diffraction,<ref name="Hristova"/> and computational methods.<ref name="Murray">{{cite journal | vauthors = Murray D, Honig B | title = Electrostatic control of the membrane targeting of C2 domains | journal = Molecular Cell | volume = 9 | issue = 1 | pages = 145–154 | date = January 2002 | pmid = 11804593 | doi = 10.1016/S1097-2765(01)00426-9 | doi-access = free }}</ref><ref name="Efremov">{{cite journal | vauthors = Efremov RG, Nolde DE, Konshina AG, Syrtcev NP, Arseniev AS | title = Peptides and proteins in membranes: what can we learn via computer simulations? | journal = Current Medicinal Chemistry | volume = 11 | issue = 18 | pages = 2421–2442 | date = September 2004 | pmid = 15379706 | doi = 10.2174/0929867043364496 }}</ref><ref name="Lomize">{{cite journal | vauthors = Lomize AL, Pogozheva ID, Lomize MA, Mosberg HI | title = Positioning of proteins in membranes: a computational approach | journal = Protein Science | volume = 15 | issue = 6 | pages = 1318–1333 | date = June 2006 | pmid = 16731967 | pmc = 2242528 | doi = 10.1110/ps.062126106 }}</ref><ref>{{cite web|vauthors=Lomize A, Lomize M, Pogozheva I |title=Comparison with experimental data | work=Orientations of Proteins in Membranes |publisher=University of Michigan |url=http://opm.phar.umich.edu/about.php?subject=experiments |access-date=2007-02-08}}</ref>

Two distinct membrane-association modes of proteins have been identified. Typical water-soluble proteins have no exposed nonpolar residues or any other hydrophobic anchors. Therefore, they remain completely in aqueous solution and do not penetrate into the lipid bilayer, which would be energetically costly. Such proteins interact with bilayers only electrostatically, for example, [[ribonuclease]] and [[poly-lysine]] interact with membranes in this mode. However, typical amphitropic proteins have various hydrophobic anchors that penetrate the interfacial region and reach the hydrocarbon interior of the membrane. Such proteins "deform" the lipid bilayer, decreasing the temperature of lipid fluid-gel transition.<ref name=Papahadjopoulos_1975>{{cite journal | vauthors = Papahadjopoulos D, Moscarello M, Eylar EH, Isac T | title = Effects of proteins on thermotropic phase transitions of phospholipid membranes | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 401 | issue = 3 | pages = 317–335 | date = September 1975 | pmid = 52374 | doi = 10.1016/0005-2736(75)90233-3 }}</ref> The binding is usually a strongly exothermic reaction.<ref name=Seelig_2004>{{cite journal | vauthors = Seelig J | title = Thermodynamics of lipid-peptide interactions | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1666 | issue = 1–2 | pages = 40–50 | date = November 2004 | pmid = 15519307 | doi = 10.1016/j.bbamem.2004.08.004 | doi-access = free }}</ref> Association of amphiphilic α-helices with membranes occurs similarly.<ref name="Hristova">{{cite journal | vauthors = Hristova K, Wimley WC, Mishra VK, Anantharamiah GM, Segrest JP, White SH | title = An amphipathic alpha-helix at a membrane interface: a structural study using a novel X-ray diffraction method | journal = Journal of Molecular Biology | volume = 290 | issue = 1 | pages = 99–117 | date = July 1999 | pmid = 10388560 | doi = 10.1006/jmbi.1999.2840 }}</ref><ref name="Darkes">{{cite journal |vauthors=Darkes MJ, Davies SM, Bradshaw JP |title=Interaction of tachykinins with phospholipid membranes: A neutron diffraction study |journal=Physica B |year=1997 |volume=241 |pages=1144–1147 |bibcode=1997PhyB..241.1144D |doi=10.1016/S0921-4526(97)00811-9}}</ref> [[Intrinsically unstructured proteins|Intrinsically unstructured]] or [[Denaturation (biochemistry)|unfolded]] peptides with nonpolar residues or lipid anchors can also penetrate the interfacial region of the membrane and reach the hydrocarbon core, especially when such peptides are cationic and interact with negatively charged membranes.<ref name="Ellena">{{cite journal | vauthors = Ellena JF, Moulthrop J, Wu J, Rauch M, Jaysinghne S, Castle JD, Cafiso DS | title = Membrane position of a basic aromatic peptide that sequesters phosphatidylinositol 4,5 bisphosphate determined by site-directed spin labeling and high-resolution NMR | journal = Biophysical Journal | volume = 87 | issue = 5 | pages = 3221–3233 | date = November 2004 | pmid = 15315949 | pmc = 1304792 | doi = 10.1529/biophysj.104.046748 | bibcode = 2004BpJ....87.3221E }}</ref><ref name="Marcotte">{{cite journal | vauthors = Marcotte I, Dufourc EJ, Ouellet M, Auger M | title = Interaction of the neuropeptide met-enkephalin with zwitterionic and negatively charged bicelles as viewed by 31P and 2H solid-state NMR | journal = Biophysical Journal | volume = 85 | issue = 1 | pages = 328–339 | date = July 2003 | pmid = 12829487 | pmc = 1303088 | doi = 10.1016/S0006-3495(03)74477-4 | bibcode = 2003BpJ....85..328M }}</ref><ref name="Zhang">{{cite journal | vauthors = Zhang W, Crocker E, McLaughlin S, Smith SO | title = Binding of peptides with basic and aromatic residues to bilayer membranes: phenylalanine in the myristoylated alanine-rich C kinase substrate effector domain penetrates into the hydrophobic core of the bilayer | journal = The Journal of Biological Chemistry | volume = 278 | issue = 24 | pages = 21459–21466 | date = June 2003 | pmid = 12670959 | doi = 10.1074/jbc.M301652200 | doi-access = free }}</ref>

==Categories==

===Enzymes===
Peripheral enzymes participate in [[metabolism]] of different membrane components, such as lipids ([[phospholipase]]s and [[cholesterol oxidase]]s), [[cell wall]] [[oligosaccharides]] ([[glycosyltransferase]] and [[transglycosidases]]), or proteins ([[signal peptidase]] and [[palmitoyl protein thioesterase]]s). [[Lipases]] can also digest lipids that form [[micelle]]s or nonpolar droplets in water.

{| class="wikitable" style="margin: 1em auto 1em auto"
!width="180"|Class
!width="275"|Function
!width="305"| Physiology
!width="50"| Structure
|-
| [[Alpha/beta hydrolase fold]] || Catalyzes the [[hydrolysis]] of chemical bonds.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00561 |title=Pfam entry Abhydrolase 1 |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929115310/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00561 |archive-date=2007-09-29 |url-status=dead }}</ref>|| Includes [[bacteria]]l, [[fungal]], gastric and pancreatic [[lipase]]s, palmitoyl protein [[thioesterase]]s, [[cutin]]ase, and [[cholinesterase]]s ||central beta sheet inserted in between two layers of alpha helices<ref>{{Cite journal |last1=Bauer |first1=Tabea L. |last2=Buchholz |first2=Patrick C. F. |last3=Pleiss |first3=Jürgen |date=March 2020 |title=The modular structure of α/β-hydrolases |journal=The FEBS Journal |language=en |volume=287 |issue=5 |pages=1035–1053 |doi=10.1111/febs.15071 |issn=1742-464X|doi-access=free |pmid=31545554 }}</ref>
|-
| [[Phospholipase A2]] (secretory and cytosolic) || Hydrolysis of sn-2 [[fatty acid]] bond of [[phospholipid]]s.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00068 |title=Pfam entry: Phospholipase A2 |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929110908/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00068 |archive-date=2007-09-29 |url-status=dead }}</ref>||Lipid digestion, membrane disruption, and [[lipid signaling]]. ||contains catalytic amino acid triad: [[aspartic acid]], [[serine]], and [[histidine]]<ref>{{Citation |last1=Casale |first1=Jarett |title=Biochemistry, Phospholipase A2 |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK534851/ |work=StatPearls |access-date=2023-11-29 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30521272 |last2=Kacimi |first2=Salah Eddine O. |last3=Varacallo |first3=Matthew}}</ref> 
|-
| [[Phospholipase C]] || Hydrolyzes PIP2, a [[phosphatidylinositol]], into two second messagers, [[inositol triphosphate]] and [[diglyceride|diacylglycerol]].<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00388 |title=Pfam entry: Phosphatidylinositol-specific phospholipase C, X domain |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929084148/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00388 |archive-date=2007-09-29 |url-status=dead }}</ref> || [[Lipid signaling]] ||core structure composed of a split [[triosephosphate isomerase]] (TIM) barrel which has an active site, catalytic residues, and a Ca<sup>2+</sup> binding site <ref>{{Citation |title=Phospholipase C |date=2023-08-16 |url=https://en.wikipedia.org/w/index.php?title=Phospholipase_C&oldid=1170655893 |work=Wikipedia |access-date=2023-11-29 |language=en}}</ref> 
|-
| [[Cholesterol oxidase]]s || [[Oxidize]]s and isomerizes [[cholesterol]] to cholest-4-en-3-one.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF09129 |title=Pfam entry: Cholesterol oxidase |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929083056/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF09129 |archive-date=2007-09-29 |url-status=dead }}</ref> || Depletes [[cellular membrane]]s of cholesterol, used in bacterial [[pathogenesis]].||two loops of residue which act as a lid on the [[active site]]<ref>{{Cite journal |last1=Yue |first1=Q. Kimberley |last2=Kass |first2=Ignatius J. |last3=Sampson |first3=Nicole S. |last4=Vrielink |first4=Alice |date=1999-04-01 |title=Crystal Structure Determination of Cholesterol Oxidase from Streptomyces and Structural Characterization of Key Active Site Mutants |url=https://pubs.acs.org/doi/10.1021/bi982497j |journal=Biochemistry |language=en |volume=38 |issue=14 |pages=4277–4286 |doi=10.1021/bi982497j |pmid=10194345 |issn=0006-2960}}</ref>
|-
| [[Carotenoid oxygenase]]|| Cleaves [[carotenoids]].<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF03055 |title=Pfam entry: Retinal pigment epithelial membrane protein |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929104832/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF03055 |archive-date=2007-09-29 |url-status=dead }}</ref>|| Carotenoids function in both plants and animals as [[hormone]]s (includes [[vitamin A]] in humans), [[pigment]]s, [[Flavor (taste)|flavor]]s, floral scents and defense compounds. ||composed of multiple enzymes attached together forming branch-like structures<ref>{{Citation |title=Carotenoid oxygenase |date=2023-11-29 |url=https://en.wikipedia.org/w/index.php?title=Carotenoid_oxygenase&oldid=1187404336 |work=Wikipedia |access-date=2023-11-29 |language=en}}</ref>
|-
| [[Lipoxygenase]]s || [[Iron]]-containing enzymes that [[catalyze]] the [[Lipoxygenase|dioxygenation]] of polyunsaturated [[fatty acid]]s.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00305 |title=Pfam entry: Lipoxygenase |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929104653/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00305 |archive-date=2007-09-29 |url-status=dead }}</ref> ||In animals lipoxygenases are involved in the synthesis of [[inflammation|inflammatory]] mediators known as [[leukotrienes]].|| hundreds of [[amino acid]]s that makes up a protein are organized into two domains: beta-sheet N terminal and helical C terminal<ref>{{Cite journal |last1=Prigge |first1=S. T. |last2=Boyington |first2=J. C. |last3=Faig |first3=M. |last4=Doctor |first4=K. S. |last5=Gaffney |first5=B. J. |last6=Amzel |first6=L. M. |date=1997-11-01 |title=Structure and mechanism of lipoxygenases |journal=Biochimie |volume=79 |issue=11 |pages=629–636 |doi=10.1016/S0300-9084(97)83495-5 |issn=0300-9084|doi-access=free |pmid=9479444 }}</ref>
|-
| [[Clostridium perfringens alpha toxin|Alpha toxin]]s || Cleave [[phospholipid]]s in the cell membrane, similar to Phospholipase C.<ref>[http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=1kho PDBsum entry: Alpha Toxin]</ref>|| Bacterial pathogenesis, particularly by ''[[Clostridium perfringens]]''. ||soluble monomer with oligomeric pre-pore complexes<ref>{{Cite web |title=Alpha Toxin - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/nursing-and-health-professions/alpha-toxin |access-date=2023-11-29 |website=www.sciencedirect.com}}</ref>
|-
| [[Sphingomyelinase]] C || A [[phosphodiesterase]], cleaves phosphodiester bonds.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01663 |title=Pfam entry: Type I phosphodiesterase |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929084034/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01663 |archive-date=2007-09-29 |url-status=dead}}</ref> || Processing of lipids such as [[sphingomyelin]].||[[Saposin protein domain|saposin]] domain and connector regions with a metallophosphate catalytic domain <ref>{{Cite journal |last1=Xiong |first1=Zi-Jian |last2=Huang |first2=Jingjing |last3=Poda |first3=Gennady |last4=Pomès |first4=Régis |last5=Privé |first5=Gilbert G. |date=2016-07-31 |title=Structure of Human Acid Sphingomyelinase Reveals the Role of the Saposin Domain in Activating Substrate Hydrolysis |url=https://www.sciencedirect.com/science/article/pii/S0022283616302200 |journal=Journal of Molecular Biology |volume=428 |issue=15 |pages=3026–3042 |doi=10.1016/j.jmb.2016.06.012 |pmid=27349982 |issn=0022-2836}}</ref>
|-
| [[Glycosyltransferase]]s: MurG and Transglycosidases || Catalyzes the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming [[glycosidic]] bonds.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00534 |title=Pfam entry: Glycosyl transferases group 1 |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929120820/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00534 |archive-date=2007-09-29 |url-status=dead }}</ref> || Biosynthesis of [[disaccharide]]s, [[oligosaccharide]]s and [[polysaccharide]]s (glycoconjugates), MurG is involved in bacterial [[peptidoglycan]] biosynthesis. || three glycine rich loops: one in the C terminal and two in the N terminal <ref>{{Cite journal |last1=Ünligil |first1=Uluğ M |last2=Rini |first2=James M |date=2000-10-01 |title=Glycosyltransferase structure and mechanism |url=https://www.sciencedirect.com/science/article/pii/S0959440X0000124X |journal=Current Opinion in Structural Biology |volume=10 |issue=5 |pages=510–517 |doi=10.1016/S0959-440X(00)00124-X |pmid=11042447 |issn=0959-440X}}</ref> 
|-
| [[Ferrochelatase]] || Converts [[protoporphyrin IX]] into [[heme]].<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00762 |title=Pfam entry: Ferrochelatase |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929120511/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00762 |archive-date=2007-09-29 |url-status=dead }}</ref> || Involved in [[porphyrin]] metabolism, [[protoporphyrin]]s are used to strengthen [[egg shell]]s. || [[polypeptide]] folded into two domains that each have a four-stranded parallel [[beta sheet]] flanked by alpha [[A-helices|helices]]<ref>{{Cite journal |last1=Al-Karadaghi |first1=Salam |last2=Hansson |first2=Mats |last3=Nikonov |first3=Stanislav |last4=Jönsson |first4=Bodil |last5=Hederstedt |first5=Lars |date=November 1997 |title=Crystal structure of ferrochelatase: the terminal enzyme in heme biosynthesis |journal=Structure |volume=5 |issue=11 |pages=1501–1510 |doi=10.1016/s0969-2126(97)00299-2 |issn=0969-2126|doi-access=free |pmid=9384565 }}</ref>
|-
| Myotubularin-related protein family || Lipid [[phosphatase]] that dephosphorylates [[Phosphatidylinositol 3-phosphate|PtdIns3P]] and [[Phosphatidylinositol (3,5)-bisphosphate|PtdIns(3,5)P2]].<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF06602 |title=Pfam entry:Myotubularin-related |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070926215455/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF06602 |archive-date=2007-09-26 |url-status=dead }}</ref>|| Required for [[muscle]] cell differentiation. ||contains a [[GRAM domain]], [[SET domain|SET]] interacting domain, and a [[PDZ domain|PDZ]] binding domain<ref>{{Cite book |title=Emery and Rimoin's Principles and Practice of Medical Genetics |url=https://www.sciencedirect.com/book/9780123838346/emery-and-rimoins-principles-and-practice-of-medical-genetics |access-date=2023-11-29 |isbn=978-0-12-383834-6 |language=en}}</ref>
|-
| [[Dihydroorotate dehydrogenase]]s || [[Oxidation]] of dihydroorotate (DHO) to orotate.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01180 |title=Pfam entry:Dihydroorotate dehydrogenase |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070926220055/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01180 |archive-date=2007-09-26 |url-status=dead }}</ref>|| Biosynthesis of [[pyrimidine]] [[nucleotide]]s in [[prokaryotic]] and [[eukaryotic]] cells. ||composed of two domains: [[Alpha beta barrel|alpha/beta barrel]] domain that contains the active site and an [[alpha-helical]] domain that forms the opening tunnel to the active site <ref>{{Cite journal |last1=Liu |first1=Shenping |last2=Neidhardt |first2=Edie A |last3=Grossman |first3=Trudy H |last4=Ocain |first4=Tim |last5=Clardy |first5=Jon |date=January 2000 |title=Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents |journal=Structure |volume=8 |issue=1 |pages=25–33 |doi=10.1016/s0969-2126(00)00077-0 |issn=0969-2126|doi-access=free |pmid=10673429 }}</ref>
|-
|[[Glycolate oxidase]] || Catalyses the [[oxidation]] of α-[[hydroxycarboxylic acid]]s to the corresponding α-[[ketoacid]]s.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01070 |title=Pfam entry: FMN-dependent dehydrogenase |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929111635/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01070 |archive-date=2007-09-29 |url-status=dead }}</ref>|| In green [[plant]]s, the enzyme participates in [[photorespiration]]. In animals, the enzyme participates in production of [[oxalate]].||β8/α8 fold containing alpha helices, beta strands, and loops and turns<ref>{{Cite web |title=Glycolate oxidase - Proteopedia, life in 3D |url=https://proteopedia.org/wiki/index.php/Glycolate_oxidase#:~:text=The%20biological%20assembly%20of%20human,are%20shown%20as%20red%20spheres. |access-date=2023-11-28 |website=proteopedia.org |language=en}}</ref>
|}

===Membrane-targeting domains (“lipid clamps")===
[[Image:1ptr.png|thumb|right|170px| [[C1 domain]] of PKC-delta (1ptr)
Middle plane of the lipid bilayer – black dots. Boundary of the hydrocarbon core region – blue dots (cytoplasmic side). Layer of lipid phosphates – yellow dots.]]
Membrane-targeting domains associate specifically with head groups of their lipid ligands embedded into the membrane. These lipid ligands are present in different concentrations in distinct types of biological membranes (for example, [[Phosphatidylinositol 3-phosphate|PtdIns3P]] can be found mostly in membranes of early [[endosome]]s, [[Phosphatidylinositol (3,5)-bisphosphate|PtdIns(3,5)P2]] in late [[endosome]]s, and [[Phosphatidylinositol 4-phosphate|PtdIns4P]] in the [[Golgi apparatus|Golgi]]).<ref name="Cho"/> Hence, each domain is targeted to a specific membrane.
*[[C1 domain]]s and [[Phorbol|phorbol esters]].
*[[C2 domain]]s bind [[phosphatidylserine]], [[phosphatidylcholine]] or [[Phosphatidylinositol (3,4)-bisphosphate|PtdIns(3,4)P2]] or [[Phosphatidylinositol (4,5)-bisphosphate|PtdIns(4,5)P2]].
*[[Pleckstrin homology domain]]s, [[PX domain]]s, and [[Tubby protein|Tubby domains]]  bind different [[Phosphatidylinositol|phosphoinositides]]
*[[FYVE domain]]s are more specific for PtdIns3P.
*[[ENTH domain]]s bind [[Phosphatidylinositol (3,4)-bisphosphate|PtdIns(3,4)P2]] or [[Phosphatidylinositol (4,5)-bisphosphate|PtdIns(4,5)P2]].
*[[ANTH]] domain binds PtdIns(4,5)P2.
*Proteins from [[Merlin (protein)|ERM (ezrin/radixin/moesin) family]] bind PtdIns(4,5)P2.
*Other [[Phosphatidylinositol|phosphoinositide]]-binding proteins include [[phosphotyrosine]]-binding domain and certain [[PDZ domain]]s. They bind PtdIns(4,5)P2.
*Discoidin domains of blood [[coagulation]] factors
*[[ENTH]], VHS and [[ANTH]] domains

===Structural domains===
Structural domains mediate attachment of other proteins to membranes. Their binding to membranes can be mediated by [[calcium]] ions (Ca<sup>2+</sup>) that form bridges between the acidic protein residues and phosphate groups of lipids, as in annexins or GLA domains.

{| class="wikitable" style="margin: 1em auto 1em auto"
!width="150"|Class
!width="275"|Function
!width="305"| Physiology
!width="50"| Structure
|-
|[[Annexin]]s || [[Calcium]]-dependent intracellular membrane/ [[phospholipid]] binding.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00191 |title=Pfam entry: Annexin |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929104531/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00191 |archive-date=2007-09-29 |url-status=dead }}</ref> || Functions include [[Vesicle (biology)|vesicle]] trafficking, membrane fusion and [[ion channel]] formation.||
|-
|[[Synapsin|Synapsin I]]|| Coats [[synaptic vesicle]]s and binds to several [[cytoskeletal]] elements.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF02078 |title=Pfam entry Synapsin N |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070926215343/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF02078 |archive-date=2007-09-26 |url-status=dead }}</ref>|| Functions in the regulation of [[neurotransmitter]] release.||
|-
|[[Synuclein]]|| Unknown cellular function.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01387 |title=Pfam entry Synuclein |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070926215944/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF01387 |archive-date=2007-09-26 |url-status=dead }}</ref>|| Thought to play a role in regulating the stability and/or turnover of the [[plasma membrane]]. Associated with both [[Parkinson's disease]] and [[Alzheimer's disease]].||
|-
|GLA-domains of the [[coagulation|coagulation system]]|| [[Gamma-carboxyglutamate]] (GLA) domains are responsible for the high-affinity binding of calcium ions.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00594 |title=Pfam entry: Gla |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070929111243/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00594 |archive-date=2007-09-29 |url-status=dead }}</ref>|| Involved in function of clotting factors in the [[Coagulation#The coagulation cascade|blood coagulation cascade.]]||
|-
| [[Spectrin]] and α-[[actinin]]-2 || Found in several cytoskeletal and [[microfilament]] proteins.<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00435 |title=Pfam entry Spectrin |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070926215853/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF00435 |archive-date=2007-09-26 |url-status=dead }}</ref> || Maintenance of [[plasma membrane]] integrity and cytoskeletal structure.||
|}

===Transporters of small hydrophobic molecules===
These peripheral proteins function as carriers of non-polar compounds between different types of cell membranes or between membranes and cytosolic protein complexes. The transported substances are phosphatidylinositol, tocopherol, gangliosides, glycolipids, sterol derivatives, retinol, fatty acids, water, macromolecules, red blood cells, phospholipids, and nucleotides.
*[[Glycolipid transfer protein]]s
*[[Lipocalin]]s including [[retinol binding protein]]s and [[fatty acid]]-binding proteins
*Polyisoprenoid-binding protein, such as [[YceI protein domain]]
*[[Ganglioside GM2 activator protein]]s
*[[CRAL-TRIO domain]] (α-[[Tocopherol]] and [[phosphatidylinositol]] sec14p transfer proteins)
*[[Sterol carrier protein]]s
*[[Steroidogenic acute regulatory protein|Phosphatidylinositol transfer proteins and STAR domains]]
*[[Oxysterol-binding protein]]

===Electron carriers===
These proteins are involved in [[electron transport chain]]s. They include [[cytochrome c]], [[Copper proteins|cupredoxins]], [[iron–sulfur protein|high potential iron protein]], adrenodoxin reductase, some [[flavoprotein]]s, and others.

===Polypeptide hormones, toxins, and antimicrobial peptides===
Many hormones, [[neurotoxin|toxins]], [[Enzyme inhibitor|inhibitor]]s, or [[antimicrobial peptides]] interact specifically with [[transmembrane protein]] complexes. They can also accumulate at the lipid bilayer surface, prior to binding their protein targets. Such polypeptide ligands are often positively charged and interact [[Ionic bond|electrostatically]] with [[anionic]] membranes.

Some water-soluble proteins and peptides can also form [[Ion channel|transmembrane channel]]s. They usually undergo [[oligomer]]ization, significant [[conformational change]]s, and associate with membranes irreversibly. 3D structure of one such transmembrane channel, [[Hemolysis (microbiology)|α-hemolysin]], has been determined. In other cases, the experimental structure represents a water-soluble conformation that interacts with the lipid bilayer peripherally, although some of the channel-forming peptides are rather hydrophobic and therefore were studied by [[NMR spectroscopy]] in organic solvents or in the presence of [[micelles]].

{| class="wikitable" style="margin: 1em auto 1em auto"
!width="100"|Class
!width="275"|Proteins
!width="655"|Physiology
|-
| [[Venom]] [[toxin]]s ||
*[[Scorpion|Scorpion venom]]
*[[Snake venom]]
*[[Conotoxins]]
*[[Poneratoxin]] (insect)
|| Well known types of biotoxins include [[neurotoxins]], [[cytotoxin]]s, [[hemotoxin]]s and [[necrotoxin]]s. Biotoxins have two primary functions: predation ([[snake]], [[scorpion]] and [[cone snail]] toxins) and defense ([[honeybee]] and [[ant]] toxins).<ref>{{cite book | veditors = Rochat H, Martin-Eauclaire MF |title=Animal toxins: facts and protocols | url=https://books.google.com/books?id=kDDWg_oJYHIC&q=peptide+venom+toxin&pg=PA149| publisher=Birkhũser Verlag |location=Basel |year=2000 |isbn=3-7643-6020-8}}</ref>
|-
| [[Sea anemone]] toxins ||
*Sea anemone [[sodium channel]] inhibitory toxin
*[[Neurotoxin|Neurotoxin III]]
*[[Cytolysin]]s
||Inhibition of sodium and [[potassium channel]]s and [[Pore forming toxins|membrane pore formation]] are the primary actions of over 40 known Sea anemone peptide toxins. Sea anemone are [[carnivorous]] animals and use toxins in [[predation]] and defense; anemone toxin is of similar [[toxicity]] as the most toxic [[organophosphate]] [[chemical warfare]] agents.<ref>{{cite web | vauthors = Patocka J, Strunecka A | date = 1999 | url = http://www.asanltr.com/ASANews-99/991b.htm | title = Sea Anemone Toxins | archive-url = https://web.archive.org/web/20130615144536/http://www.asanltr.com/ASANews-99/991b.htm | archive-date= 15 June 2013 | work = The ASA Newsletter }}</ref>
|-
| [[Bacterial]] toxins ||
*[[Clostridium perfringens|Perfringolysin O]]
*[[Botulinum toxin]] B
*Heat-stable [[enterotoxin]] B
*δ-[[Endotoxin]]s
*[[Bacteriocin]]s, such as [[microcin]])
*[[Lantibiotic]] peptides, such as [[nisin]])
*[[Gramicidin S]]
||[[Microbial]] toxins are the primary [[virulence factor]]s for a variety of [[pathogenic]] bacteria. Some toxins, are [[Pore forming toxins]] that lyse cellular membranes. Other toxins inhibit [[Protein biosynthesis|protein synthesis]] or activate [[second messenger]] pathways causing dramatic alterations to [[signal transduction]] pathways critical in maintaining a variety of cellular functions. Several bacterial toxins can act directly on the [[immune system]], by acting as [[superantigen]]s and causing massive [[T cell]] [[Cell growth|proliferation]], which overextends the immune system. Botulinum toxin is a neurotoxin that prevents neuro-secretory vesicles from docking/fusing with the nerve [[synapse]] plasma membrane, inhibiting [[neurotransmitter]] release.<ref>{{cite journal | vauthors = Schmitt CK, Meysick KC, O'Brien AD | title = Bacterial toxins: friends or foes? | journal = Emerging Infectious Diseases | volume = 5 | issue = 2 | pages = 224–234 | year = 1999 | pmid = 10221874 | pmc = 2640701 | doi = 10.3201/eid0502.990206 }}</ref>
|-
| [[Fungal]] toxins ||
*Cyclic [[lipopeptide]] antibiotics<br/> [[Surfactin]] and [[daptomycin]]
*[[Peptaibol]]s
||These peptides are characterized by the presence of an unusual amino acid, [[2-Aminoisobutyric acid|α-aminoisobutyric acid]], and exhibit [[antibiotic]] and [[Fungicide|antifungal]] properties due to their membrane channel-forming activities.<ref>{{cite journal | vauthors = Chugh JK, Wallace BA | title = Peptaibols: models for ion channels | journal = Biochemical Society Transactions | volume = 29 | issue = Pt 4 | pages = 565–570 | date = August 2001 | pmid = 11498029 | doi = 10.1042/BST0290565 }}</ref>
|-
|[[Antimicrobial peptide]]s ||
*[[Helicobacter pylori|HP]] peptide
*[[Saposin]] B and [[NK-lysin]]
*[[Lactoferricin]] B
*[[Magainin]], and [[Pleurocidin]]
||The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with [[metabolism]], and targeting [[cytoplasm]]ic components. In contrast to many conventional antibiotics these peptides appear to be [[bacteriocidal]] instead of [[bacteriostatic]].
|-
| [[Defensin]]s ||
*[[Insect defensin]]s
*[[Plant defensin]]s, including [[Cyclotides]] and [[thionin]]s
||Defensins are a type of antimicrobial peptide; and are an important component of virtually all [[innate immune system|innate host defenses]] against microbial invasion. Defensins penetrate microbial cell membranes by way of electrical attraction, and form a pore in the membrane allowing efflux, which ultimately leads to the lysis of microorganisms.<ref>{{cite journal | vauthors = Oppenheim JJ, Biragyn A, Kwak LW, Yang D | title = Roles of antimicrobial peptides such as defensins in innate and adaptive immunity | journal = Annals of the Rheumatic Diseases | volume = 62 | issue = Suppl 2 | pages = ii17–ii21 | date = November 2003 | pmid = 14532141 | pmc = 1766745 | doi = 10.1136/ard.62.suppl_2.ii17 }}</ref>
|-
| [[Neuronal]] peptides ||
*[[Tachykinin]] peptides
||These proteins excite neurons, evoke [[behavioral]] responses, are potent [[Vasodilation|vasodilatator]]s, and are responsible for contraction in many types of [[smooth muscle]].<ref>{{Cite web |url=http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF02202 |title=Pfam entry Tachykinin |access-date=2007-01-25 |archive-url=https://web.archive.org/web/20070926215842/http://www.sanger.ac.uk//cgi-bin/Pfam/getacc?PF02202 |archive-date=2007-09-26 |url-status=dead}}</ref>
|-
| [[Apoptosis]] regulators ||
*[[Bcl-2]]
|| Members of the Bcl-2 family govern [[mitochondria]]l outer membrane permeability. Bcl-2 itself suppresses apoptosis in a variety of cell types including [[lymphocyte]]s and [[neurons|neuronal cell]]s.
|}

== See also ==
* [[Lipoprotein]]s
* [[Membrane protein]]s

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin}}
* {{cite book | veditors = Tamm LK |title=Protein-Lipid Interactions: From Membrane Domains to Cellular Networks| url=https://books.google.com/books?visbn=3527311513 |publisher=John Wiley & Sons |location=Chichester |year=2005 |isbn=3-527-31151-3}}
* {{cite journal | vauthors = Cho W, Stahelin RV | title = Membrane-protein interactions in cell signaling and membrane trafficking | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 34 | issue = 1 | pages = 119–151 | date = June 2005 | pmid = 15869386 | doi = 10.1146/annurev.biophys.33.110502.133337 | name-list-style = amp }}
* {{cite journal | vauthors = Goñi FM | title = Non-permanent proteins in membranes: when proteins come as visitors (Review) | journal = Molecular Membrane Biology | volume = 19 | issue = 4 | pages = 237–245 | year = 2002 | pmid = 12512770 | doi = 10.1080/0968768021000035078 | s2cid = 20892603 }}
* {{cite journal | vauthors = Johnson JE, Cornell RB | title = Amphitropic proteins: regulation by reversible membrane interactions (review) | journal = Molecular Membrane Biology | volume = 16 | issue = 3 | pages = 217–235 | year = 1999 | pmid = 10503244 | doi = 10.1080/096876899294544 | doi-access = free }}
* {{cite book | vauthors = Seaton BA, Roberts MF | chapter = Peripheral membrane proteins | pages = 355–403 | title = Biological Membranes | veditors = Mertz K, Roux B | publisher = Birkhauser | location = Boston, MA | date = 1996 }}
* {{cite book | vauthors = Benga G | chapter = Protein-lipid interactions in biological membranes | pages = 159–188 | title = Structure and Properties of Biological Membranes | volume = 1 | veditors = Benga G | location = Boca Raton, FL | publisher = CRC Press | date = 1985 }}
* {{cite journal | vauthors = Kessel A, Ben-Tal N | title = Free energy determinants of peptide association with lipid bilayers. | journal = Current Topics in Membranes | date = January 2002 | volume = 52 | pages = 205–253 | doi = 10.1016/S1063-5823(02)52010-X | isbn = 9780121533526 }}
* {{cite journal | vauthors = Malmberg NJ, Falke JJ | title = Use of EPR power saturation to analyze the membrane-docking geometries of peripheral proteins: applications to C2 domains | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 34 | issue = 1 | pages = 71–90 | year = 2005 | pmid = 15869384 | pmc = 3637887 | doi = 10.1146/annurev.biophys.34.040204.144534 }}
* {{cite journal | vauthors = McIntosh TJ, Simon SA | title = Roles of bilayer material properties in function and distribution of membrane proteins | journal = Annual Review of Biophysics and Biomolecular Structure | volume = 35 | issue = 1 | pages = 177–198 | year = 2006 | pmid = 16689633 | doi = 10.1146/annurev.biophys.35.040405.102022 }}
{{refend}}

== External links ==
*[https://opm.phar.umich.edu/types/2 Peripheral membrane proteins] in [[OPM database]]
*[http://www.mrc-lmb.cam.ac.uk/genomes/dolop/ DOLOP] Genomics-oriented database of bacterial lipoproteins
*[http://www.cryst.bbk.ac.uk/peptaibol/home.shtml Peptaibol database]
*[http://aps.unmc.edu/AP/main.php Antimicrobial Peptide Database] {{Webarchive|url=https://web.archive.org/web/20110720093645/http://aps.unmc.edu/AP/main.php |date=2011-07-20 }}

{{Cell membranes}}

[[Category:Peripheral membrane proteins]]