Membrane protein

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Crystal structure of Potassium channel Kv1.2/2.1 Chimera. Calculated hydrocarbon boundaries of the lipid bilayer are indicated by red and blue dots.

Membrane proteins are proteins that interact with biological membranes. They are targets of over 50% of all modern medicinal drugs.[1] It is estimated that 20–30% of all genes in most genomes encode membrane proteins.[2]

Function[edit]

Membrane proteins perform a variety of functions vital to the survival of organisms:[3]

Topology[edit]

The topology of an integral membrane protein describes the number of transmembrane segments, as well as the orientation in the membrane.[4] Membrane proteins have several different topologies:[5]

A slightly different classification is to divide all membrane proteins to integral and amphitropic.[6] 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[edit]

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. They can be classified according to their relationship with the bilayer:

  • 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[edit]

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.

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

Polypeptide toxins[edit]

Main article: Pore-forming toxin

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.

3D Structure[edit]

Increase in the number of 3D structures of membrane proteins known

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.[7]

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.[8] As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20-30% of the total proteome.[9]

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.[10] Coevolution information has been successfully exploited for prediction of multiple large (membrane) protein structures.[11][12][13]

Due to this difficulty and the importance of this class of proteins methods of protein structure prediction based on hydropathy plots and the positive inside rule have been developed.[14][15]

See also[edit]

External links[edit]

Organizations[edit]

Membrane protein databases[edit]

Further reading[edit]

References[edit]

  1. ^ 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. 
  2. ^ 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.  edit
  3. ^ 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.  edit
  4. ^ Von Heijne, G. (2006). "Membrane-protein topology". Nature Reviews Molecular Cell Biology 7 (12): 909–918. doi:10.1038/nrm2063. PMID 17139331.  edit
  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. 
  6. ^ 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. 
  7. ^ White, Stephen. "General Principle of Membrane Protein Folding and Stability." Stephen White Laboratory Homepage. 10 Nov. 2009. web.
  8. ^ 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.  edit
  9. ^ Membrane Proteins of known 3D Structure
  10. ^ Cross, Timothy, Mukesh Sharma, Myunggi Yi, Huan-Xiang Zhou (2010). "Influence of Solubilizing Environments on Membrane Protein Structures"
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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.  edit
  15. ^ State of the art in membrane protein prediction