Editing Lipid-anchored protein

{{Short description|Membrane protein}}
{{also|Proteolipid}}
[[File:0303 Lipid Bilayer With Various Components.jpg|thumb|525x525px|Lipid membrane with various proteins]]
'''Lipid-anchored proteins''' (also known as '''lipid-linked proteins''') are [[protein]]s that are [[Covalent bond|covalently]] attached to [[lipid]]s embedded into [[biological membranes]]. The lipid-anchored protein can be located on either side of the cell membrane. Thus, the lipid serves to anchor the protein to the cell membrane.<ref name="Karp2009">{{cite book|author = Gerald Karp|title = Cell and Molecular Biology: Concepts and Experiments|url = https://books.google.com/books?id=arRGYE0GxRQC&pg=PA128|access-date = 13 November 2010|year = 2009|publisher = John Wiley and Sons|isbn = 978-0-470-48337-4|pages = 128–}}</ref><ref name=":0">{{cite book | first1 = Donald | last1 = Voet | first2 = Judith G | last2 = Voet | first3 = Charlotte W | last3 = Pratt | name-list-style = vanc |title = Fundamentals of Biochemistry: Life at the Molecular Level |publisher = John Wiley & Sons, Inc.|year = 2013|isbn = 978-0470-54784-7|pages = 263|edition = 4th}}</ref> Such proteins are a type of [[proteolipid]]s.

The lipid groups contribute to the intracellular localization and the biological function of the protein to which they are attached.<ref name=":0" /> The lipid serves as a mediator of the protein association with specific biological membranes and protein-protein interactions.<ref name=":1" /><ref name=":2" /> The lipidation can also sequester a protein away from its substrate to inactivate the protein and then activate it by [[substrate presentation]].

Overall, there are three main types of lipid-anchored proteins which include '''prenylated proteins''', '''fatty acylated proteins''' and '''glycosylphosphatidylinositol-linked proteins (GPI)'''.<ref name=":0" /><ref>{{cite journal | vauthors = Ferguson MA | title = Lipid anchors on membrane proteins. | journal = Current Opinion in Structural Biology | date = August 1991 | volume = 1 | issue = 4 | pages = 522–9 | doi=10.1016/s0959-440x(05)80072-7}}</ref> A protein can have multiple lipid groups covalently attached to specific [[amino acid residues]].<ref name=":0" />

== Prenylated proteins ==
[[File:Isoprene.svg|thumb|143x143px|Isoprene unit]]
[[Prenylation|Prenylated]] proteins are proteins with covalently attached hydrophobic [[isoprene]] polymers (i.e. branched five-carbon hydrocarbon<ref>{{Cite web|url = http://medical-dictionary.thefreedictionary.com/isoprene|title = Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, Seventh Ed|date = 2003|access-date = 28 November 2015|last = isoprene}}</ref>) at cysteine residues of the protein.<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Casey PJ, Seabra MC | title = Protein prenyltransferases | journal = The Journal of Biological Chemistry | volume = 271 | issue = 10 | pages = 5289–92 | date = March 1996 | pmid = 8621375 | doi = 10.1074/jbc.271.10.5289 | doi-access = free }}</ref> More specifically, these isoprenoid groups, usually [[farnesylation|farnesyl]] (15-carbon) and [[Geranylgeranylation|geranylgeranyl]] (20-carbon) are attached to the protein via thioether linkages at cysteine residues near the C terminal of the protein.<ref name=":1" /><ref name=":2">{{cite journal | vauthors = Novelli G, D'Apice MR | title = Protein farnesylation and disease | journal = Journal of Inherited Metabolic Disease | volume = 35 | issue = 5 | pages = 917–26 | date = September 2012 | pmid = 22307208 | doi = 10.1007/s10545-011-9445-y | s2cid = 11555502 }}</ref> This prenylation of lipid chains to proteins facilitate their interaction with the cell membrane.<ref name="Karp2009" />
[[File:Caaxbox.JPG|left|thumb|Caax Box|240x240px]]
The [[prenylation]] motif “CaaX box” is the most common prenylation site in proteins, that is, the site where farnesyl or geranylgeranyl covalently attach.<ref name=":0" /><ref name=":1" /> In the CaaX box sequence, the C represents the cysteine that is prenylated, the A represents any [[Aliphatic compound|aliphatic]] amino acid and the X determines the type of prenylation that will occur. If the X is an Ala, Met, Ser or Gln the protein will be farnesylated via the [[farnesyltransferase]] enzyme and if the X is a Leu then the protein will be geranylgeranylated via the [[Geranylgeranyltransferase type 1|geranylgeranyltransferase I]] enzyme.<ref name=":1" /><ref name=":2" /> Both of these enzymes are similar with each containing two subunits.<ref name=":8">{{cite journal | vauthors = Lane KT, Beese LS | title = Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I | journal = Journal of Lipid Research | volume = 47 | issue = 4 | pages = 681–99 | date = April 2006 | pmid = 16477080 | doi = 10.1194/jlr.R600002-JLR200 | doi-access = free }}</ref>

=== Roles and function ===
[[File:Synthesis of geranyl pyrophosphate.png|thumb|Prenylation chains (e.g. [[geranyl pyrophosphate]])]]
Prenylated proteins are particularly important for eukaryotic cell growth, differentiation and morphology.<ref name=":8" /> Furthermore, protein prenylation is a reversible post-translational modification to the cell membrane. This dynamic interaction of prenylated proteins with the cell membrane is important for their signalling functions and is often deregulated in disease processes such as cancer.<ref>{{cite journal | vauthors = Stein V, Kubala MH, Steen J, Grimmond SM, Alexandrov K | title = Towards the systematic mapping and engineering of the protein prenylation machinery in Saccharomyces cerevisiae | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0120716 | date = 2015-01-01 | pmid = 25768003 | pmc = 4358939 | doi = 10.1371/journal.pone.0120716 | bibcode = 2015PLoSO..1020716S | doi-access = free }}</ref> More specifically, [[Ras subfamily|Ras]] is the protein that undergoes prenylation via [[farnesyltransferase]] and when it is switched on it can turn on genes involved in cell growth and differentiation. Thus overactiving Ras signalling can lead to cancer.<ref>{{cite journal | vauthors = Goodsell DS | title = The molecular perspective: the ras oncogene | journal = The Oncologist | volume = 4 | issue = 3 | pages = 263–4 | date = 1999-01-01 | doi = 10.1634/theoncologist.4-3-263 | pmid = 10394594 | doi-access = free }}</ref> An understanding of these prenylated proteins and their mechanisms have been important for the drug development efforts in combating cancer.<ref>{{cite journal | vauthors = Reuter CW, Morgan MA, Bergmann L | title = Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? | journal = Blood | volume = 96 | issue = 5 | pages = 1655–69 | date = September 2000 | pmid = 10961860 | doi = 10.1182/blood.V96.5.1655 }}</ref> Other prenylated proteins include members of the [[Rab (G-protein)|Rab]] and Rho families as well as [[lamin]]s.<ref name=":8" />

Some important prenylation chains that are involved in the [[HMG-CoA reductase]] [[metabolic pathway]]<ref name="Karp2009" /> are [[geranylgeraniol]], [[farnesol]] and [[dolichol]]. These isoprene polymers (e.g. [[geranyl pyrophosphate]] and [[farnesyl pyrophosphate]]) are involved in the condensations via enzymes such as [[prenyltransferase]] that eventually cyclizes to form [[cholesterol]].<ref name=":0" />

== Fatty acylated proteins ==

'''Fatty [[Acylation|acylated]] proteins''' are proteins that have been post-translationally modified to include the covalent attachment of fatty acids at certain amino acid residues.<ref name=":3">{{cite journal | vauthors = Resh MD | title = Trafficking and signaling by fatty-acylated and prenylated proteins | journal = Nature Chemical Biology | volume = 2 | issue = 11 | pages = 584–90 | date = November 2006 | pmid = 17051234 | doi = 10.1038/nchembio834 | s2cid = 9734759 }}</ref><ref name=":4">{{cite journal | vauthors = Wilson JP, Raghavan AS, Yang YY, Charron G, Hang HC | title = Proteomic analysis of fatty-acylated proteins in mammalian cells with chemical reporters reveals S-acylation of histone H3 variants | journal = Molecular & Cellular Proteomics | volume = 10 | issue = 3 | pages = M110.001198 | date = March 2011 | pmid = 21076176 | pmc = 3047146 | doi = 10.1074/mcp.M110.001198  |doi-access=free }}</ref> The most common fatty acids that are covalently attached to the protein are the saturated [[Myristic acid|myristic]] (14-carbon) acid and [[Palmitic acid|palmitic]] acid (16-carbon). Proteins can be modified to contain either one or both of these fatty acids.<ref name=":3" />[[File:Myristoylation.pdf|thumb|219x219px|
Myristoylation
]]

=== ''N-''myristoylation ===
''N''-myristoylation (i.e. attachment of myristic acid) is generally an irreversible protein modification that typically occurs during protein synthesis<ref name=":3" /><ref name=":5">{{cite journal | vauthors = Farazi TA, Waksman G, Gordon JI | title = The biology and enzymology of protein N-myristoylation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 43 | pages = 39501–4 | date = October 2001 | pmid = 11527981 | doi = 10.1074/jbc.R100042200 | doi-access = free }}</ref> in which the myrisitc acid is attached to the α-amino group of an [[N-terminal]] glycine residue through an [[amide linkage]].<ref name=":0" /><ref name=":4" /> This reaction is facilitated by [[N-myristoyltransferase 1|''N''-myristoyltransferase]] . These proteins usually begin with a {{abbr|Met|Methionine}}-{{abbr|Gly|Glycine}} sequence and with either a serine or [[threonine]] at position 5.<ref name=":3" /> Proteins that have been myristoylated are involved in [[signal transduction cascade]], protein-protein interactions and in mechanisms that regulate protein targeting and function.<ref name=":5" /> An example in which the myristoylation of a protein is important is in [[apoptosis]], programmed cell death. After the protein [[BH3 interacting-domain death agonist]] (Bid) has been myristoylated, it targets the protein to move to the mitochondrial membrane to release [[cytochrome c]], which then ultimately leads to cell death.<ref>{{cite journal | vauthors = Martin DD, Beauchamp E, Berthiaume LG | title = Post-translational myristoylation: Fat matters in cellular life and death | journal = Biochimie | volume = 93 | issue = 1 | pages = 18–31 | date = January 2011 | pmid = 21056615 | doi = 10.1016/j.biochi.2010.10.018 | series = Bioactive Lipids, Nutrition and Health }}</ref> Other proteins that are myristoylated and involved in the regulation of apoptosis are [[actin]] and [[gelsolin]].

=== ''S''-palmitoylation ===
[[File:Palmitoylation.png|thumb|292x292px|Palmitoylation]]
S-palmitoylation (i.e. attachment of palmitic acid) is a reversible protein modification in which a palmitic acid is attached to a specific cysteine residue via [[thioester]] linkage.<ref name=":0" /><ref name=":3" /> The term [[S-acylation]] can also be used when other medium and long fatty acids chains are also attached to palmitoylated proteins. No consensus sequence for protein palmitoylation has been identified.<ref name=":3" /> Palmitoylated proteins are mainly found on the cytoplasmic side of the plasma membrane where they play a role in transmembrane signaling.  The palmitoyl group can be removed by palmitoyl thioesterases. It is believed that this reverse palmitoylation may regulate the interaction of the protein with the membrane and thus have a role in signaling processes.<ref name=":0" /> Furthermore, this allows for the regulation of protein subcellular localization, stability and trafficking.<ref>{{cite journal | vauthors = Aicart-Ramos C, Valero RA, Rodriguez-Crespo I | title = Protein palmitoylation and subcellular trafficking | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1808 | issue = 12 | pages = 2981–94 | date = December 2011 | pmid = 21819967 | doi = 10.1016/j.bbamem.2011.07.009 | doi-access =  }}</ref> An example in which palmitoylation of a protein plays a role in cell signaling pathways is in the clustering of proteins in the [[synapse]]. When the [[PSD-95|postsynaptic density protein 95 (PSD-95)]] is palmitoylated, it is restricted to the membrane and allows it to bind to and cluster ion channels in the [[postsynaptic]] membrane. Thus, palmitoylation can play a role in the regulation of neurotransmitter release.<ref>{{Cite book|title = Molecular Mechanisms of Synaptogenesis|last = Dityatev|first = Alexander|publisher = Springer|year = 2006|location = New York|pages = 72–75|editor-last = El-Husseini|editor-first = Alaa}}</ref>

Palmitoylation mediates the affinity of a protein for [[lipid rafts]] and facilitates the clustering of proteins.<ref>{{cite journal |last1=Levental |first1=I. |last2=Lingwood |first2=D. |last3=Grzybek |first3=M. |last4=Coskun |first4=U. |last5=Simons |first5=K. |title=Palmitoylation regulates raft affinity for the majority of integral raft proteins |journal=Proceedings of the National Academy of Sciences |date=3 December 2010 |volume=107 |issue=51 |pages=22050–22054 |doi=10.1073/pnas.1016184107|pmid=21131568 |pmc=3009825 |bibcode=2010PNAS..10722050L |doi-access=free }}</ref> The clustering can increase the proximity of two molecules. Alternatively, clustering can sequester a protein away from a substrate. For example, palmitoylation of phospholipase D (PLD) sequesters the enzyme away from its substrate phosphatidylcholine. When cholesterol levels decrease or PIP2 levels increase the [[palmitate mediated localization]] is disrupted, the enzyme trafficks to PIP2 where it encounters its substrate and is active by [[substrate presentation]].<ref>{{cite journal |last1=Petersen |first1=EN |last2=Chung |first2=HW |last3=Nayebosadri |first3=A |last4=Hansen |first4=SB |title=Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D. |journal=Nature Communications |date=15 December 2016 |volume=7 |pages=13873 |doi=10.1038/ncomms13873 |pmid=27976674|pmc=5171650 |bibcode=2016NatCo...713873P }}</ref><ref>{{cite journal |last1=Robinson |first1=CV |last2=Rohacs |first2=T |last3=Hansen |first3=SB |title=Tools for Understanding Nanoscale Lipid Regulation of Ion Channels. |journal=Trends in Biochemical Sciences |date=September 2019 |volume=44 |issue=9 |pages=795–806 |doi=10.1016/j.tibs.2019.04.001 |pmid=31060927|pmc=6729126 }}</ref><ref>{{cite journal |last1=Petersen |first1=EN |last2=Pavel |first2=MA |last3=Wang |first3=H |last4=Hansen |first4=SB |title=Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels. |journal=  Biochimica et Biophysica Acta (BBA) - Biomembranes|date=28 October 2019 |volume=1862 |issue=1 |pages=183091 |doi=10.1016/j.bbamem.2019.183091 |pmid=31672538|pmc=6907892 |doi-access=free }}</ref>

== GPI proteins ==
[[File:Glycophosphatidylinositol anchor.tif|thumb|490x490px|Structure of the glycophosphatidylinositol anchor in the plasma membrane of a eukaryotic cell]]
'''Glycosylphosphatidylinositol-anchored proteins (GPI-anchored proteins)''' are attached to a GPI complex molecular group via an [[amide linkage]] to the protein's [[C-terminus|C-terminal]] carboxyl group.<ref name=":6">{{cite journal | vauthors = Kinoshita T, Fujita M | title = Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling | journal = Journal of Lipid Research | volume = 57 | issue = 1 | pages = 6–24 | date = January 2016 | pmid = 26563290 | pmc = 4689344 | doi = 10.1194/jlr.R063313  |doi-access=free }}</ref> This GPI complex consists of several main components that are all interconnected: a [[phosphoethanolamine]], a linear [[tetrasaccharide]] (composed of three [[mannose]] and a glucosaminyl) and a [[phosphatidylinositol]].<ref name=":7">{{Cite journal|title = Glycosylphosphatidylinositol (GPI)-Anchored Proteins|journal = Biological and Pharmaceutical Bulletin|date = 2002-01-01|pages = 409–417|volume = 25|issue = 4|doi = 10.1248/bpb.25.409|pmid = 11995915|first = Hiroh|last = Ikezawa|doi-access = free}}</ref> The [[phosphatidylinositol]] group is [[Glycosidic bond|glycosidically]] linked to the non-N-acetylated glucosamine of the tetrasaccharide. A [[phosphodiester bond]] is then formed between the mannose at the [[Nonreducing sugar|nonreducing]] end (of the tetrasaccaride) and the [[phosphoethanolamine]]. The phosphoethanolamine is then amide linked to the C-terminal of the [[Carboxylic acid|carboxyl]] group of the respective protein.<ref name=":0" /> The GPI attachment occurs through the action of GPI-transamidase complex.<ref name=":7" /> The fatty acid chains of the phosphatidylinositol are inserted into the membrane and thus are what anchor the protein to the membrane.<ref>{{cite journal | vauthors = Kinoshita T, Fujita M | title = Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling | journal = Journal of Lipid Research | volume = 57 | issue = 1 | pages = 6–24 | date = January 2016 | pmid = 26563290 | pmc = 4689344 | doi = 10.1194/jlr.R063313  |doi-access=free | url = http://www.jlr.org/content/early/2015/11/12/jlr.R063313 }}</ref> These proteins are only located on the exterior surface of the plasma membrane.<ref name=":0" />

=== Roles and function ===
The sugar residues in the tetrasaccaride and the fatty acid residues in the [[phosphatidylinositol]] group vary depending on the protein.<ref name=":0" /> This great diversity is what allows the GPI proteins to have a wide range of functions including acting as [[hydrolytic enzyme]]s, [[adhesion molecule]], receptors, [[Protease inhibitor (biology)|protease inhibitor]] and complement regulatory proteins.<ref>{{cite journal | vauthors = Kinoshita T | title = Biosynthesis and deficiencies of glycosylphosphatidylinositol | journal = Proceedings of the Japan Academy. Series B, Physical and Biological Sciences | volume = 90 | issue = 4 | pages = 130–43 | year = 2014 | pmid = 24727937 | pmc = 4055706 | doi = 10.2183/pjab.90.130 | bibcode = 2014PJAB...90..130K }}</ref> Furthermore, GPI proteins play an important in embryogenesis, development, neurogenesis, the immune system and fertilization.<ref name=":6" /> More specifically, the GPI protein [[IZUMO1R]] (also named JUNO after the [[Juno (mythology)|Roman goddess of fertility]]) on the egg plasma has an essential role in [[Fertilisation|sperm-egg fusion]]. Releasing the IZUMO1R (JUNO) GPI protein from the egg plasma membrane does not allow for sperm to fuse with the egg and it is suggested that this mechanism may contribute to the polyspermy block at the plasma membrane in eggs.<ref>{{cite journal | vauthors = Coonrod SA, Naaby-Hansen S, Shetty J, Shibahara H, Chen M, White JM, Herr JC | title = Treatment of mouse oocytes with PI-PLC releases 70-kDa (pI 5) and 35- to 45-kDa (pI 5.5) protein clusters from the egg surface and inhibits sperm-oolemma binding and fusion | journal = Developmental Biology | volume = 207 | issue = 2 | pages = 334–49 | date = March 1999 | pmid = 10068467 | doi = 10.1006/dbio.1998.9161 | doi-access = free }}</ref> Other roles that GPI modification allows for is in the association with membrane microdomains, transient [[homodimerization]] or in apical sorting in polarized cells.<ref name=":6" />

== References ==
{{Reflist}}

== External links ==
*{{Commons category-inline}}

{{Cell membranes}}

{{DEFAULTSORT:Lipid Anchored Protein}}
[[Category:Membrane biology]]
[[Category:Membrane proteins]]
[[Category:Lipoproteins]]
[[Category:Post-translational modification]]