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Transmembrane protein

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.

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Types

There are two basic types of transmembrane proteins:

Alpha-helical. These proteins are present in all types of biological membranes including outer membranes. This is the major category of transmembrane proteins.
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

Stability of α-helical transmembrane proteins

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

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

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

Light absorption-driven transporters

Bacteriorhodopsin-like proteins including rhodopsin (see also opsin)[2]
Bacterial photosynthetic reaction centres and photosystems I and II [3]
Light harvesting complexes from bacteria and chloroplasts [4]

Oxidoreduction-driven transporters

Transmembrane cytochrome b-like proteins [5]: coenzyme Q - cytochrome c reductase (cytochrome bc1 ); cytochrome b6f complex; formate dehydrogenase, respiratory nitrate reductase; succinate - coenzyme Q reductase (fumarate reductase); and succinate dehydrogenase. See electron transport chain.
Cytochrome c oxidases [6] from bacteria and mitochondria

Electrochemical potential-driven transporters

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

P-P-bond hydrolysis-driven transporters

P-type calcium ATPase (five different conformations) [8]
Calcium ATPase regulators phospholamban and sarcolipin[9]
ABC transporters: BtuCD, multidrug transporter, and molybdate uptake transporter
General secretory pathway (Sec) translocon (preprotein translocase SecY) [10]

Porters (uniporters, symporters, antiporters)

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

Voltage-gated ion channel like, including potassium channels KcsA and KvAP, and inward-rectifier potassium ion channel Kirbac [19]
Large-conductance mechanosensitive channel, MscL [20]
Small-conductance mechanosensitive ion channel (MscS) [21]
CorA metal ion transporters [22]
Ligand-gated ion channel of neurotransmitter receptors (acetylcholine receptor) [23]
Aquaporins [24]
Chloride channels [25]
Outer membrane auxiliary proteins (polysaccharide transporter) [26] - α-helical transmembrane proteins from the outer bacterial membrane

Enzymes

Methane monooxygenase [27]
Rhomboid protease [28]
Disulfide bond formation protein (DsbA-DsbB complex) [29]

Proteins with alpha-helical transmembrane anchors

T cell receptor transmembrane dimerization domain [30]
Cytochrome c nitrite reductase complex [31]
Steryl-sulfate sulfohydrolase [32]
Stannin [33]
Glycophorin A dimer [34]
Inovirus (filamentous phage) major coat protein [35]
Pilin [36]
Pulmonary surfactant-associated protein [37]
Monoamine oxidases A and B [38],
Cytochrome P450 oxidases [39],
Corticosteroid 11β-dehydrogenases [40].
Signal Peptide Peptidase [41]
Membrane protease specific for a stomatin homolog [42]

β-Barrels composed by a single polypeptide chain

Beta barrels from eight beta-strands and with "shear number" of ten (n=8, S=10) [43]. They include:
- OmpA-like transmembrane domain (OmpA),
- Virulence-related outer membrane protein family (OmpX),
- Outer membrane protein W family (OmpW),
- Antimicrobial peptide resistance and lipid A acylation protein family (PagP)
- Lipid A deacylase PagL, and
- Opacity family porins (NspA)
Autotransporter domain (n=12,S=14') [44]
FadL outer membrane protein transport family, including Fatty acid transporter FadL (n=14,S=14) [45]
General bacterial porin family, known as trimeric porins (n=16,S=20) [46]
Maltoporin, or sugar porins (n=18,S=22) [47]
Nucleoside-specific porin (n=12,S=16) [48]
Outer membrane phospholipase A1(n=12,S=16) [49]
TonB dependent receptors and their plug domain. They are ligand-gated outer membrane channels (n=22,S=24), including cobalamin transporter BtuB, Fe(III)-pyochelin receptor FptA, receptor FepA, ferric hydroxamate uptake receptor FhuA, transporter FecA, and pyoverdine receptor FpvA [50]
Outer membrane protein OpcA family (n=10,S=12) that includes outer membrane protease OmpT and adhesin/invasin OpcA protein [51]
Outer membrane protein G porin family (n=14,S=16) [52]

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

β-barrels composed by several polypeptide chains

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

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

Some cell adhesion proteins
Some receptor proteins
Insulin receptor
GLUTI
Integrin
Cadherin