Membrane protein

Membrane protein

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 one of the common types of protein along with soluble globular proteins, fibrous proteins, and disordered proteins.[1] They are targets of over 50% of all modern medicinal drugs.[2] It is estimated that 20–30% of all genes in most genomes encode membrane proteins.[3]

Contents

  • Function 1
  • Topology 2
    • Integral membrane proteins 2.1
    • Peripheral membrane proteins 2.2
    • Polypeptide toxins 2.3
  • 3D Structure 3
  • Membrane proteins in genomes 4
  • See also 5
  • External links 6
    • Organizations 6.1
    • Membrane protein databases 6.2
    • Further reading 6.3
  • References 7

Function

Membrane proteins perform a variety of functions vital to the survival of organisms:[4]

Topology

The topology of an integral membrane protein describes the number of transmembrane segments, as well as the orientation in the membrane.[5] Membrane proteins have several different topologies:[6]

A slightly different classification is to divide all membrane proteins to integral and amphitropic.[7] Amphitropic proteins 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

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

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

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

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.[8]

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.[9] As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20-30% of the total proteome.[10]

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.[11] Coevolution information has been successfully exploited for prediction of multiple large (membrane) protein structures.[12][13][14]

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.[15][16]

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.[17] The membrane localization has been confirmed for more than 600 of them experimentally.[17] 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.

See also

External links

Organizations

  • Membrane Protein Structural Dynamics Consortium

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

Further reading

  • The Human Membrane Proteome - A comprehensive article covering the transmembrane protein component of the human proteome

References

  1. ^ Andreeva, A (2014). "SCOP2 prototype: a new approach to protein structure mining". Nucleic Acids Res.  
  2. ^ Overington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?". Nat Rev Drug Discov 5 (12): 993–6.  
  3. ^  
  4. ^ 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.  
  5. ^ Von Heijne, G. (2006). "Membrane-protein topology". Nature Reviews Molecular Cell Biology 7 (12): 909–918.  
  6. ^ Gerald Karp (2009). Cell and Molecular Biology: Concepts and Experiments. John Wiley and Sons. pp. 128–.  
  7. ^ Johnson JE, Cornell RB (1999). "Amphitropic proteins: regulation by reversible membrane interactions (review)". Mol. Membr. Biol. 16 (3): 217–235.  
  8. ^ White, Stephen. "General Principle of Membrane Protein Folding and Stability." Stephen White Laboratory Homepage. 10 Nov. 2009. web.
  9. ^ 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.  
  10. ^ Membrane Proteins of known 3D Structure
  11. ^ Cross, Timothy, Mukesh Sharma, Myunggi Yi, Huan-Xiang Zhou (2010). "Influence of Solubilizing Environments on Membrane Protein Structures"
  12. ^ 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.  
  13. ^ Marks DS, Colwell LJ, Sheridan R, et al. (2011). "Protein 3D structure computed from evolutionary sequence variation" 6 (12). pp. e28766.  
  14. ^ Flock T, Venkatakrishnan A, Vinothkumar K, Babu MM (June 2012). "Deciphering membrane protein structures from protein sequences" 13 (6). p. 160.  
  15. ^ Elofsson, A.; Heijne, G. V. (2007). "Membrane Protein Structure: Prediction versus Reality". Annual Review of Biochemistry 76: 125–140.  
  16. ^ State of the art in membrane protein prediction
  17. ^ a b 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.