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A transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

File:Polytopic membrane protein.png

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

Types[edit | edit source]

There are two basic types of transmembrane proteins:

  1. Alpha-helical. These proteins are present in all types of biological membranes including outer membranes. This is the major category of transmembrane proteins.
  2. Beta-barrels. These proteins are found only in outer membranes of Gram-negative bacteria, cell wall of Gram-positive bacteria, and outer membranes of mitochondria and chloroplasts. All beta-barrel transmembrane proteins have simplest up-and-down topology, which may reflect their common evolutionary origin and similar folding mechanism.

Thermodynamic stability and folding[edit | edit source]

Stability of α-helical transmembrane proteins[edit | edit source]

Transmembrane α-helical proteins are unusually stable judging from thermal denaturation studies, because they do not unfold completely within the membranes (the complete unfolding would require breaking down too many α-helical H-bonds in the nonpolar media). On the other hand, these proteins easily misfold, due to non-native aggregation in membranes, transition to the molten globule states, formation of non-native disulfide bonds, or unfolding of peripheral regions and nonregular loops that are locally less stable.

It is also important to properly define the unfolded state. The unfolded state of membrane proteins in detergent micelles is different from that in the thermal denaturation experiments. This state represents a combination of folded hydrophobic α-helices and partially unfolded segments covered by the detergent. For example, the "unfolded" bacteriorhodopsin in SDS micelles has four transmembrane α-helices folded, while the rest of the protein is situated at the micelle-water interface and can adopt different types of non-native amphiphilic structures. Free energy differences between such detergent-denatured and native states are similar to stabilities of water-soluble proteins (< 10 kcal/mol).

Folding of α-helical transmembrane proteins[edit | edit source]

Refolding of α-helical transmembrane proteins in vitro is technically difficult. There are relatively few examples of the successful refolding experiments, as for bacteriorhodopsin. In vivo all such proteins are normally folded co-translationally within the large transmembrane translocon. The translocon channel provides a highly heterogeneous environment for the nascent transmembane α-helices. A relatively polar amphiphilic α-helix can adopt a transmembrane orientation in the translocon (although it would be at the membrane surface or unfolded in vitro), because its polar residues can face the central water-filled channel of the translocon. Such mechanism is necessary for incorporation of polar α-helices into structures of transmembrane proteins. The amphiphilic helices remain attached to the translocon until the protein is completely synthesized and folded. If the protein remains unfolded and attached to the translocon for too long, it is degraded by specific "quality control" cellular systems.

Stability and folding of β-barrel transmembrane proteins[edit | edit source]

Stability of β-barrel transmembrane proteins is similar to stability of water-soluble proteins, based on chemical denaturation studies. Their folding in vivo is facilitated by water-soluble chaperones, such as protein Skp [1].

3D structures[edit | edit source]

Light absorption-driven transporters[edit | edit source]

Oxidoreduction-driven transporters[edit | edit source]

Electrochemical potential-driven transporters[edit | edit source]

  • Proton or sodium translocating F-type and V-type ATPases [7]

P-P-bond hydrolysis-driven transporters[edit | edit source]

Porters (uniporters, symporters, antiporters)[edit | edit source]

  • Mitochondrial carrier proteins [11]
  • Major Facilitator Superfamily (Glycerol-3-hosphate transporter, Lactose permease, and Multidrug transporter EmrD) [12]
  • Resistance-nodulation-cell division (multidrug efflux transporter AcrB, see multidrug resistance)[13]
  • Dicarboxylate/amino acid:cation symporter (proton glutamate symporter) [14]
  • Monovalent cation/proton antiporter (Sodium/proton antiporter 1 NhaA) [15]
  • Neurotransmitter sodium symporter [16]
  • Ammonia transporters [17]
  • Drug/Metabolite Transporter (small multidrug resistance transporter EmrE - the structures are retracted as erroneous) [18]

Alpha-helical channels including ion channels[edit | edit source]

Enzymes[edit | edit source]

Proteins with alpha-helical transmembrane anchors[edit | edit source]

β-barrels composed of a single polypeptide chain[edit | edit source]

Note: n and S are, respectively, the number of beta-strands and the "shear number" [53] of the beta-barrel

β-barrels composed of several polypeptide chains[edit | edit source]

  • Trimeric autotransporter (n=12,S=12) [54]
  • Outer membrane efflux proteins, also known as trimeric outer membrane factors (n=12,S=18) including TolC and multidrug resistance proteins [55]
  • MspA porin (octamer, n=S=16) and α-hemolysin (heptamer n=S=14) [56]. These proteins are secreted.

See also Gramicidin A [57], a peptide that forms a dimeric transmembrane β-helix. It is also secreted by Gram-positive bacteria.

References[edit | edit source]

  • Booth, P.J., Templer, R.H., Meijberg, W., Allen, S.J., Curran, A.R., and Lorch, M. 2001. In vitro studies of membrane protein folding. Crit. Rev. Biochem. Mol. Biol. 36: 501-603.
  • Bowie J.U. 2001. Stabilizing membrane proteins. Curr. Op. Struct. Biol. 11: 397-402.
  • Bowie J.U. 2005. Solving the membrane protein folding problem. Nature 438: 581-589.
  • DeGrado W.F., Gratkowski H. and Lear J.D. 2003. How do helix-helix interactions help determine the folds of membrane proteins? Perspectives from the study of homo-oligomeric helical bundles. Protein Sci. 12: 647-665.
  • Lee, A.G. 2003 Lipid-protein interactions in biological membranes: a structural perspective. Biochim. Biophys. Acta 1612: 1-40.
  • Lee, A.G. 2004. How lipids affect the activities of integral membrane proteins. Biochim. Biophys. Acta 1666: 62-87.
  • le Maire, M., Champeil, P., and Moller, J.V. 2000. Interaction of membrane proteins and lipids with solubilizing detergents. Biochim. Biophys. Acta 1508: 86-111.
  • Popot J-L. and Engelman D.M. 2000. Helical membrane protein folding, stability, and evolution. Annu. Rev. Biochem. 69: 881-922.
  • Protein-lipid interactions (Ed. L.K. Tamm) Wiley, 2005.
  • Tamm, L.K., Hong, H., and Liang, B.Y. 2004. Folding and assembly of beta-barrel membrane proteins. Biochim. Biophys. Acta 1666: 250-263.

Additional examples[edit | edit source]

External links[edit | edit source]

See also[edit | edit source]

Transporter Classification database

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