Membrane proteins are common proteins that 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 a cell membrane and can either penetrate the membrane (transmembrane) or associate with one or the other side of a membrane (integral monotopic). Peripheral membrane proteins are transiently associated with the cell membrane.

Membrane protein complexes of photosynthesis in the thylakoid 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 membrane protein structures remains a challenge in large part due to the difficulty in establishing experimental conditions that can preserve the correct (native) conformation of the protein in isolation from its native environment.

Function

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

The localization of proteins in membranes can be predicted reliably using hydrophobicity analyses of protein sequences, i.e. the localization of hydrophobic amino acid sequences.

Integral membrane proteins

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Schematic representation of transmembrane proteins: 1. a single transmembrane α-helix (bitopic membrane protein) 2. a polytopic transmembrane α-helical protein 3. a polytopic transmembrane β-sheet protein
The membrane is represented in light-brown.

Integral membrane proteins are permanently attached to the membrane. Such proteins can be separated from the biological membranes only using detergents, nonpolar solvents, or sometimes denaturing agents.[citation needed] They can be classified according to their relationship with the bilayer:

Peripheral membrane proteins

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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 ionic interactions with membrane lipids (e.g. through a calcium ion)

Peripheral membrane proteins are temporarily attached either to the lipid bilayer or to integral proteins by a combination of hydrophobic, electrostatic, and other non-covalent interactions. Peripheral proteins dissociate following treatment with a polar reagent, such as a solution with an elevated pH or high salt concentrations.[citation needed]

Integral and peripheral proteins may be post-translationally modified, with added fatty acid, diacylglycerol[8] or prenyl chains, or GPI (glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.

Polypeptide toxins

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Polypeptide toxins and many antibacterial peptides, such as colicins or hemolysins, and certain proteins involved in apoptosis, are sometimes considered a separate category. These proteins are water-soluble but can undergo significant conformational changes, form oligomeric complexes and associate irreversibly or reversibly with the lipid bilayer.

In genomes

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Membrane proteins, like soluble globular proteins, fibrous proteins, and disordered proteins, are common.[9] It is estimated that 20–30% of all genes in most genomes encode for membrane proteins.[10][11] For instance, about 1000 of the ~4200 proteins of E. coli are 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 the genome encodes membrane proteins.[13]

In disease

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Membrane proteins are the targets of over 50% of all modern medicinal drugs.[1] Among the human diseases in which membrane proteins have been implicated are heart disease, Alzheimer's and cystic fibrosis.[13]

Purification of membrane proteins

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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] Their hydrophobic surfaces make structural and especially functional characterization difficult.[13][16] Detergents can be used to render membrane proteins water-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 with hydrophilic ones, taking great care to maintain secondary structure while revising overall charge.[13]

Affinity chromatography is one of the best solutions for purification of membrane proteins. The polyhistidine-tag is a commonly used tag for membrane protein purification,[17] and the alternative rho1D4 tag has also been successfully used.[18][19]

See also

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References

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  1. ^ a b Overington 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.
  2. ^ 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. PMC 2739160. PMID 19678920.
  3. ^ 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. 
  4. ^ 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.
  5. ^ Gerald Karp (2009). Cell and Molecular Biology: Concepts and Experiments. John Wiley and Sons. pp. 128–. ISBN 978-0-470-48337-4. Retrieved 13 November 2010 – via Google Books.
  6. ^ 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 Elsevier Science Direct.
  7. ^ 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. PMC 5525207. PMID 28738801. 
  8. ^ 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. PMC 6004266. PMID 29695868.
  9. ^ 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. PMC 3964979. PMID 24293656.
  10. ^ 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.
  11. ^ 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 from the original (PDF) on 2020-08-04 – via Semantic Scholar. 
  12. ^ 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. 
  13. ^ a b c d e f Martin, 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. 
  14. ^ 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. PMC 2580798. PMID 18674618.
  15. ^ 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 from the original (PDF) on 2020-08-04 – via Semantic Scholar. 
  16. ^ Rawlings AE (June 2016). "Membrane proteins: always an insoluble problem?". Biochemical Society Transactions. 44 (3): 790–5. doi:10.1042/BST20160025. PMC 4900757. PMID 27284043.
  17. ^ 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.
  18. ^ 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. PMC 3779079. PMID 23777860.
  19. ^ 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. PMC 2715541. PMID 19581598.

Further reading

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Organizations

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Membrane protein databases

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