Membrane protein

Membrane proteinsare commonproteinsthat are part of, or interact with,biological membranes.Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of acell membraneand can either penetrate the membrane (transmembrane) or associate with one or the other side of a membrane (integral monotopic).Peripheral membrane proteinsare transiently associated with the cell membrane.

Membrane proteins are common, and medically important—about a third of all human proteins are membrane proteins, and these are targets for more than half of all drugs.^[1]Nonetheless, compared to other classes of proteins, determining membraneprotein structuresremains a challenge in large part due to the difficulty in establishing experimental conditions that can preserve the correct (native)conformation of the proteinin isolation from its native environment.

Function[edit]

Membrane proteins perform a variety of functions vital to the survival of organisms:^[2]

Membrane receptorproteins relay signals between the cell'sinternalandexternalenvironments.
Transport proteinsmove molecules andionsacross the membrane. They can be categorized according to theTransporter Classification database.
Membraneenzymesmay have many activities, such asoxidoreductase,transferaseorhydrolase.^[3]
Cell adhesion moleculesallow cells to identify each other and interact. For example, proteins involved inimmune response

The localization of proteins in membranes can be predicted reliably usinghydrophobicity analysesof protein sequences, i.e. the localization ofhydrophobic amino acidsequences.

Integral membrane proteins[edit]

Integral membrane proteinsare permanently attached to the membrane. Such proteins can be separated from the biological membranes only usingdetergents,nonpolar solvents,or sometimesdenaturingagents.^{[citation needed]}They can be classified according to their relationship with thebilayer:

Integral polytopic proteinsare transmembrane proteins that span across the membrane more than once. These proteins may have differenttransmembrane topology.^[4]^[5]These proteins have one of two structural architectures:
- Helix bundleproteins, which are present in all types ofbiological membranes;
- Beta barrelproteins, which are found only inouter membranesofGram-negative bacteria,and outer membranes ofmitochondriaandchloroplasts.^[6]
Bitopic proteinsare transmembrane proteins that span across the membrane only once. Transmembrane helices from these proteins have significantly different amino acid distributions to transmembrane helices from polytopic proteins.^[7]
Integral monotopic proteinsare integral membrane proteins that are attached to only one side of the membrane and do not span the whole way across.

Peripheral membrane proteins[edit]

Peripheral membrane proteinsare temporarily attached either to thelipid bilayeror to integral proteins by a combination ofhydrophobic,electrostatic,and other non-covalent interactions. Peripheral proteins dissociate following treatment with a polar reagent, such as a solution with an elevatedpHor high salt concentrations.^{[citation needed]}

Integral and peripheral proteins may be post-translationally modified, with addedfatty acid,diacylglycerol^[8]orprenylchains, orGPI(glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.

Polypeptide toxins[edit]

Polypeptidetoxins and manyantibacterial peptides,such ascolicinsorhemolysins,and certain proteins involved inapoptosis,are sometimes considered a separate category. These proteins arewater-solublebut can undergo significantconformational changes,formoligomeric complexesand associateirreversiblyor reversibly with thelipid bilayer.

In genomes[edit]

Membrane proteins, like solubleglobular proteins,fibrous proteins,anddisordered proteins,are common.^[9]It is estimated that 20–30% of allgenesin mostgenomesencode for membrane proteins.^[10]^[11]For instance, about 1000 of the ~4200 proteins ofE. coliare thought to be membrane proteins, 600 of which have been experimentally verified to be membrane resident.^[12]In humans, current thinking suggests that fully 30% of thegenomeencodes membrane proteins.^[13]

In disease[edit]

Membrane proteins are thetargetsof over 50% of all modernmedicinal drugs.^[1]Among the human diseases in which membrane proteins have been implicated areheart disease,Alzheimer'sandcystic fibrosis.^[13]

Purification of membrane proteins[edit]

Although membrane proteins play an important role in all organisms, their purification has historically, and continues to be, a huge challenge for protein scientists. In 2008, 150 unique structures of membrane proteins were available,^[14]and by 2019 only 50 human membrane proteins had had their structures elucidated.^[13]In contrast, approximately 25% of all proteins are membrane proteins.^[15]Theirhydrophobicsurfaces make structural and especially functional characterization difficult.^[13]^[16]Detergentscan be used to render membrane proteinswater-soluble,but these can also alter protein structure and function.^[13]Making membrane proteins water-soluble can also be achieved through engineering the protein sequence, replacing selected hydrophobic amino acids withhydrophilicones, taking great care to maintain secondary structure while revising overall charge.^[13]

Affinity chromatographyis one of the best solutions for purification of membrane proteins. Thepolyhistidine-tagis a commonly used tag for membrane protein purification,^[17]and the alternative rho1D4 tag has also been successfully used.^[18]^[19]

References[edit]

^^a ^bOverington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?".Nature Reviews. Drug Discovery(Opinion).5(12): 993–6.doi:10.1038/nrd2199.PMID 17139284.S2CID 11979420.
^Almén MS, Nordström KJ, Fredriksson R, Schiöth HB (August 2009)."Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin".BMC Biology.7:50.doi:10.1186/1741-7007-7-50.PMC2739160.PMID 19678920.
^Lin Y, Fuerst O, Granell M, Leblanc G, Lórenz-Fonfría V, Padrós E (August 2013)."The substitution of Arg149 with Cys fixes the melibiose transporter in an inward-open conformation".Biochimica et Biophysica Acta (BBA) - Biomembranes.1828(8): 1690–9.doi:10.1016/j.bbamem.2013.03.003.PMID 23500619– via Elsevier Science Direct.
^von Heijne G(December 2006). "Membrane-protein topology".Nature Reviews. Molecular Cell Biology.7(12): 909–18.doi:10.1038/nrm2063.PMID 17139331.S2CID 22218266.
^Gerald Karp (2009).Cell and Molecular Biology: Concepts and Experiments.John Wiley and Sons.pp. 128–.ISBN 978-0-470-48337-4.Retrieved13 November2010– viaGoogle Books.
^Selkrig J, Leyton DL, Webb CT, Lithgow T (August 2014)."Assembly of β-barrel proteins into bacterial outer membranes".Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.1843(8): 1542–50.doi:10.1016/j.bbamcr.2013.10.009.PMID 24135059– via ElsevierScience Direct.
^Baker JA, Wong WC, Eisenhaber B, Warwicker J, Eisenhaber F (July 2017)."Charged residues next to transmembrane regions revisited:" Positive-inside rule "is complemented by the" negative inside depletion/outside enrichment rule "".BMC Biology.15(1): 66.doi:10.1186/s12915-017-0404-4.PMC5525207.PMID 28738801.
^Sun C, Benlekbir S, Venkatakrishnan P, Wang Y, Hong S, Hosler J, Tajkhorshid E, Rubinstein JL, Gennis RB (May 2018)."Structure of the alternative complex III in a supercomplex with cytochrome oxidase".Nature.557(7703): 123–126.Bibcode:2018Natur.557..123S.doi:10.1038/s41586-018-0061-y.PMC6004266.PMID 29695868.
^Andreeva A, Howorth D, Chothia C, Kulesha E, Murzin AG (January 2014)."SCOP2 prototype: a new approach to protein structure mining".Nucleic Acids Research.42(Database issue): D310-4.doi:10.1093/nar/gkt1242.PMC3964979.PMID 24293656.
^Liszewski K (1 October 2015)."Dissecting the Structure of Membrane Proteins".Genetic Engineering & Biotechnology News(paper).35(17): 1, 14, 16–17.doi:10.1089/gen.35.17.02.
^Krogh A,Larsson B,von Heijne G,Sonnhammer EL (January 2001)."Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes"(PDF).Journal of Molecular Biology.305(3): 567–80.doi:10.1006/jmbi.2000.4315.PMID 11152613.S2CID 15769874.Archived fromthe original(PDF)on 2020-08-04 – viaSemantic Scholar.
^Daley DO, Rapp M, Granseth E, Melén K, Drew D, von Heijne G (May 2005). "Global topology analysis of the Escherichia coli inner membrane proteome".Science(Report).308(5726): 1321–3.Bibcode:2005Sci...308.1321D.doi:10.1126/science.1109730.PMID 15919996.S2CID 6942424.
^^a ^b ^c ^d ^e ^fMartin, Joseph; Sawyer, Abigail (2019)."Elucidating the Structure of Membrane Proteins".Tech News.BioTechniques(Print issue).66(4). Future Science: 167–170.doi:10.2144/btn-2019-0030.PMID 30987442.
^Carpenter EP, Beis K, Cameron AD, Iwata S (October 2008)."Overcoming the challenges of membrane protein crystallography".Current Opinion in Structural Biology.18(5): 581–6.doi:10.1016/j.sbi.2008.07.001.PMC2580798.PMID 18674618.
^Krogh A, Larsson B, von Heijne G, Sonnhammer EL (January 2001)."Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes"(PDF).Journal of Molecular Biology.305(3): 567–80.doi:10.1006/jmbi.2000.4315.PMID 11152613.S2CID 15769874.Archived fromthe original(PDF)on 2020-08-04 – via Semantic Scholar.
^Rawlings AE (June 2016)."Membrane proteins: always an insoluble problem?".Biochemical Society Transactions.44(3): 790–5.doi:10.1042/BST20160025.PMC4900757.PMID 27284043.
^Hochuli E, Bannwarth W, Döbeli H, Gentz R, Stüber D (November 1988). "Genetic Approach to Facilitate Purification of Recombinant Proteins with a Novel Metal Chelate Adsorbent".Nature Biotechnology.6(11): 1321–1325.doi:10.1038/nbt1188-1321.S2CID 9518666.
^Locatelli-Hoops SC, Gorshkova I, Gawrisch K, Yeliseev AA (October 2013)."Expression, surface immobilization, and characterization of functional recombinant cannabinoid receptor CB2".Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics.1834(10): 2045–56.doi:10.1016/j.bbapap.2013.06.003.PMC3779079.PMID 23777860.
^Cook BL, Steuerwald D, Kaiser L, Graveland-Bikker J, Vanberghem M, Berke AP, Herlihy K, Pick H, Vogel H, Zhang S (July 2009)."Large-scale production and study of a synthetic G protein-coupled receptor: human olfactory receptor 17-4".Proceedings of the National Academy of Sciences of the United States of America.106(29): 11925–30.Bibcode:2009PNAS..10611925C.doi:10.1073/pnas.0811089106.PMC2715541.PMID 19581598.

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