Membrane proteins are proteins that interact with biological membranes. They are targets of over 50% of all modern medicinal drugs. It is estimated that 20–30% of all genes in most genomes encode membrane proteins.
Membrane proteins perform a variety of functions vital to the survival of organisms:
- Membrane receptor proteins relay signals between the cell's internal and external environments.
- Transport proteins move molecules and ions across the membrane. They can be categorized according to the Transporter Classification database.
- Membrane enzymes may have many activities, such as oxidoreductase, transferase or hydrolase.
- Cell adhesion molecules allow cells to identify each other and interact. For example proteins involved in immune response.
A slightly different classification is to divide all membrane proteins to integral and amphitropic. The amphitropic are proteins that can exist in two alternative states: a water-soluble and a lipid bilayer-bound. The amphitropic protein category includes water-soluble channel-forming polypeptide toxins, which associate irreversibly with membranes, but excludes peripheral proteins that interact with other membrane proteins rather than with lipid bilayer.
Integral membrane proteins
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. They can be classified according to their relationship with the bilayer:
- Integral polytopic proteins, also known as "transmembrane proteins," are integral membrane proteins that span across the membrane at least once. They have one of two tertiary structures:
- Integral monotopic proteins are integral membrane proteins that are attached to only one side of the membrane and do not span the whole way across.
Peripheral membrane proteins
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.
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 aggregate and associate irreversibly with the lipid bilayer and become reversibly or irreversibly membrane-associated.
The most common tertiary structures are helix bundle and beta barrel. The portion of the membrane proteins that are attached to the lipid bilayer (see annular lipid shell) are consisting of hydrophobic amino acids only. This is done so that the peptide bonds' carbonyl and amine will react with each other instead of the hydrophobic surrounding. The portion of the protein that is not touching the lipid bilayer and is protruding out of the cell membrane are usually hydrophilic amino acids.
Membrane proteins have hydrophobic surfaces, are relatively flexible and are expressed at relatively low levels. This creates difficulties in obtaining enough protein and then growing crystals. Hence, despite the significant functional importance of membrane proteins, determining atomic resolution structures for these proteins is more difficult than globular proteins. As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20-30% of the total proteome.
Many of the successful membrane protein structures are characterized by X-ray crystallography and are very large structures in which the interactions with the membrane mimetic environments can be anticipated to be small in comparison to those within the protein structures. The small domains are particularly sensitive to the influence of membrane mimetic environments, with potential to lead to non-native structures. However, there are many sample preparation conditions that can be chosen for crystallization and for solution NMR. All membrane protein structural biology should be subjected to careful scrutiny; through a combination of structural methodologies it should be possible to achieve an understanding of the native functional state for membrane protein structures. Coevolution information has been successfully exploited for prediction of multiple large (membrane) protein structures.
Membrane proteins in genomes
A large fraction of all proteins are thought to be membrane proteins. For instance, about 1000 of the ~4200 proteins of E. coli are thought to be membrane proteins. The membrane localization has been confirmed for more than 600 of them experimentally. The localization of proteins in membranes can be predicted very reliably using hydrophobicity analyses of protein sequences, i.e. the localization of hydrophobic amino acid sequences.
- Integral membrane proteins
- Transmembrane proteins
- Peripheral membrane proteins
- Annular lipid shell
- Ion pump (biology)
- Carrier protein
- Ion channel
- Receptor (biochemistry) * List of MeSH codes (D12.776)
- Inner nuclear membrane proteins
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Membrane protein databases
- TCDB - Transporter Classification database, a comprehensive classification of transmembrane transporter proteins
- Orientations of Proteins in Membranes (OPM) database 3D structures of integral and peripheral membrane proteins arranged in the lipid bilayer
- Protein Data Bank of Transmembrane Proteins 3D models of all transmembrane proteins currently in PDB. Approximate positions of membrane boundary planes were calculated for each PDB entry.
- TransportDB Genomics-oriented database of transporters from TIGR
- Membrane PDB Database of 3D structures of integral membrane proteins and hydrophobic peptides with an emphasis on crystallization conditions
- List of transmembrane proteins of known 3D structure, incomplete list of transmembrane proteins currently used in to the Protein Data Bank
- Membrane targeting domains (MeTaDoR), a database of membrane targeting domains
- The Human Membrane Proteome - A comprehensive article covering the transmembrane protein component of the human proteome
- Overington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?". Nat Rev Drug Discov 5 (12): 993–6. doi:10.1038/nrd2199. PMID 17139284.
- Krogh, A.; Larsson, B. R.; Von Heijne, G.; Sonnhammer, E. L. L. (2001). "Predicting transmembrane protein topology with a hidden markov model: Application to complete genomes". Journal of Molecular Biology 305 (3): 567–580. doi:10.1006/jmbi.2000.4315. PMID 11152613.
- Almén, M.; Nordström, K. J.; Fredriksson, R.; Schiöth, H. B. (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.
- Von Heijne, G. (2006). "Membrane-protein topology". Nature Reviews Molecular Cell Biology 7 (12): 909–918. doi:10.1038/nrm2063. PMID 17139331.
- 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.
- Johnson JE, Cornell RB (1999). "Amphitropic proteins: regulation by reversible membrane interactions (review)". Mol. Membr. Biol. 16 (3): 217–235. doi:10.1080/096876899294544. PMID 10503244.
- White, Stephen. "General Principle of Membrane Protein Folding and Stability." Stephen White Laboratory Homepage. 10 Nov. 2009. web.
- Carpenter, E. P.; Beis, K.; Cameron, A. D.; Iwata, S. (2008). "Overcoming the challenges of membrane protein crystallography". Current Opinion in Structural Biology 18 (5): 581–586. doi:10.1016/j.sbi.2008.07.001. PMC 2580798. PMID 18674618.
- Membrane Proteins of known 3D Structure
- Cross, Timothy, Mukesh Sharma, Myunggi Yi, Huan-Xiang Zhou (2010). "Influence of Solubilizing Environments on Membrane Protein Structures"
- Hopf TA, Colwell LJ, Sheridan R, Rost B, Sander C, Marks DS (June 2012). "Three-dimensional structures of membrane proteins from genomic sequencing" 149 (7). pp. 1607–21. doi:10.1016/j.cell.2012.04.012. PMC 3641781. PMID 22579045.
- Marks DS, Colwell LJ, Sheridan R et al. (2011). "Protein 3D structure computed from evolutionary sequence variation" 6 (12). pp. e28766. doi:10.1371/journal.pone.0028766. PMC 3233603. PMID 22163331.
- Flock T, Venkatakrishnan A, Vinothkumar K, Babu MM (June 2012). "Deciphering membrane protein structures from protein sequences" 13 (6). p. 160. doi:10.1186/gb-2012-13-6-160. PMID 22738306.
- Elofsson, A.; Heijne, G. V. (2007). "Membrane Protein Structure: Prediction versus Reality". Annual Review of Biochemistry 76: 125–140. doi:10.1146/annurev.biochem.76.052705.163539. PMID 17579561.
- State of the art in membrane protein prediction
- Daley, D. O.; Rapp, M; Granseth, E; Melén, K; Drew, D; von Heijne, G (2005). "Global topology analysis of the Escherichia coli inner membrane proteome". Science 308 (5726): 1321–3. doi:10.1126/science.1109730. PMID 15919996.