Editing Peripheral membrane protein (section)

==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>