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.

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.

Contents

Types

There are two basic types of transmembrane proteins:

  1. Alpha-helical. These proteins are present in the inner membranes of bacterial cells or the plasma membrane of eukaryotes, and sometimes in the outer membranes [1] This is the major category of transmembrane proteins. In human, 27% of all proteins have been estimated to be alpha-helical membrane proteins[2].
  2. Beta-barrels. These proteins are so far 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.

Another classification refers to the position of the N- and C-terminal domains. Types I,II and III are single pass molecules, while type IV are multiple pass molecules. Type I transmembrane proteins are anchored to the lipid membrane with a stop-transfer anchor sequence and have their N-terminal domains targeted to the ER lumen during synthesis (and the extracellular space, if mature forms are located on plasmalemma). Type II and III are anchored with a signal-anchor sequence, with type II being targeted to the ER lumen with its C-terminal domain, while type III have their N-terminal domains targeted to the ER lumen. Type IV is subdivided into IV-A, with their N-terminal domains targeted to the cytozol and IV-B, with a N-terminal domain targeted to the lumen. [3]. The implications for the division in the four types are especially manifest at the time of translocation and ER-bound translation, when the protein has to be passed through the ER membrane in a direction dependent on the type.

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

Oxidoreduction-driven transporters

Electrochemical potential-driven transporters

P-P-bond hydrolysis-driven transporters

Porters (uniporters, symporters, antiporters)

Alpha-helical channels including ion channels

Enzymes

Proteins with alpha-helical transmembrane anchors

β-barrels composed of a single polypeptide chain

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

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

References

  1. ↑ alpha-helical proteins in outer membranes include Stannin and certain lipoproteins, and others
  2. ↑ Almén MS, Nordström KJ, Fredriksson R, Schiöth HB. "Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin", BMC Biol. 2009 Aug 13;7:50. PMID:19678920
  3. ↑ Harvey Lodish etc.; Molecular Cell Biology, Sixth edition, p.546
  4. ↑ Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (November 2002). "Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling". Science (journal) 298 (5599): 1793–6. doi:10.1126/science.1076535. PMID 12459591. 

Additional examples

External links

See also

Protein: cell membrane proteins (membrane glycoproteins, Integral membrane proteins/transmembrane protein, Peripheral membrane protein/Lipid-anchored protein (other than Cell surface receptor, enzymes, and cytoskeleton)
Arrestin
SAG, ARRB1, ARRB2, ARR3
Myelin
Myelin basic protein (PMP2) · Myelin proteolipid protein (PLP1) · Myelin oligodendrocyte glycoprotein · Myelin-associated glycoprotein · Myelin protein zero
Pore-forming toxin
antimicrobial cationic peptide (Cathelicidin, Defensin, Dermcidin, Histatin HTN1 HTN3) · Perforin
Transfer/transport
Membrane transport proteins (Connexin) · Phospholipid transfer proteins · Vesicular transport proteins
Pulmonary surfactant
Pulmonary surfactant-associated protein B · Pulmonary surfactant-associated protein C
Eph receptor
EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6
Other/ungrouped
Calnexin · LDL-receptor-related protein associated protein · Membrane fusion protein (VAMP) · Neurofibromin 2 · Presenilin (PSEN1, PSEN2) · Tetraspanin (TSPAN2, TSPAN3) · HFE
see also
memb/ceme: cead, icha, /prpu, trns (, )

Transporter Classification database