A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...

and 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. The peptide sequence that spans the membrane, or the transmembrane segment, is largely hydrophobic and can be visualized using the hydropathy plot. Depending on the number of transmembrane segments, transmembrane proteins can be classified as single-span (or bitopic) or multi-span (polytopic). Some other integral membrane proteins are called monotopic, meaning that they are also permanently attached to the membrane, but do not pass through it.

Types

Classification by structure

There are two basic types of transmembrane proteins:

alpha-helical The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ea ...

and beta barrels. Alpha-helical proteins are present in the inner membranes of bacterial cells or the plasma membrane of eukaryotic cells, and sometimes in the bacterial outer membrane. This is the major category of transmembrane proteins. In humans, 27% of all proteins have been estimated to be alpha-helical membrane proteins. Beta-barrel proteins are so far found only in outer membranes of gram-negative bacteria,

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...

s of gram-positive bacteria, outer membranes of

mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

and chloroplasts, or can be secreted as pore-forming toxins. All beta-barrel transmembrane proteins have simplest up-and-down topology, which may reflect their common evolutionary origin and similar folding mechanism. In addition to the protein domains, there are unusual transmembrane elements formed by peptides. A typical example is gramicidin A, a peptide that forms a dimeric transmembrane β-helix. This peptide is secreted by gram-positive bacteria as an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

. A transmembrane polyproline-II helix has not been reported in natural proteins. Nonetheless, this structure was experimentally observed in specifically designed artificial peptides.

Classification by topology

This classification refers to the position of the protein N- and C-termini on the different sides of the lipid bilayer. Types I, II, III and IV are single-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

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...

(ER) lumen during synthesis (and the extracellular space, if mature forms are located on

cell membranes The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

). 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 cytosol and IV-B, with an N-terminal domain targeted to the lumen. 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. Group 1 and 2 transmembrane protein

3D structure

Membrane protein structures can be determined by X-ray crystallography, electron microscopy or

NMR spectroscopy Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fi ...

. The most common tertiary structures of these proteins are transmembrane

helix bundle A helix bundle is a small protein fold composed of several alpha helices that are usually nearly parallel or antiparallel to each other. Three-helix bundles Three-helix bundles are among the smallest and fastest known cooperatively folding stru ...

and beta barrel. The portion of the membrane proteins that are attached to the lipid bilayer (see annular lipid shell) consist mostly of hydrophobic amino acids.White, Stephen. "General Principle of Membrane Protein Folding and Stability". Stephen White Laboratory Homepage. 10 Nov. 2009. web. Membrane proteins which 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. As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20–30% of the total proteome. Due to this difficulty and the importance of this class of proteins methods of protein structure prediction based on hydropathy plots, the positive inside rule and other methods have been developed.

Thermodynamic stability and folding

Stability of alpha-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 In molecular biology, the term molten globule (MG) refers to protein states that are more or less compact (hence the "globule"), but are lacking the specific tight packing of amino acid residues which creates the solid state-like tertiary struc ...

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 transmembrane 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 beta-barrel transmembrane proteins

Stability of beta barrel (β-barrel) transmembrane proteins is similar to stability of water-soluble proteins, based on chemical denaturation studies. Some of them are very stable even in chaotropic agents and high temperature. Their folding ''in vivo'' is facilitated by water-soluble chaperones, such as protein Skp. It is thought that β-barrel membrane proteins come from one ancestor even having different number of sheets which could be added or doubled during evolution. Some studies show a huge sequence conservation among different organisms and also conserved amino acids which hold the structure and help with folding.

3D structures

Light absorption-driven transporters

* Bacteriorhodopsin-like proteins including rhodopsin (see also

opsin Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become Retinylidene proteins, but are usually still called opsins regardless. Most ...

) *Bacterial photosynthetic reaction centres and

photosystem Photosystems are functional and structural units of protein complexes involved in photosynthesis. Together they carry out the primary photochemistry of photosynthesis: the absorption of light and the transfer of energy and electrons. Photosy ...

s I and II * Light-harvesting complexes from

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

and chloroplasts

Oxidoreduction-driven transporters

*Transmembrane cytochrome b-like proteins:

coenzyme Q - cytochrome c reductase A cofactor is a non- protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that as ...

(cytochrome bc1 );

cytochrome b6f complex The cytochrome ''b''6''f'' complex (plastoquinol—plastocyanin reductase; ) is an enzyme found in the thylakoid membrane in chloroplasts of plants, cyanobacteria, and green algae, that catalyzes the transfer of electrons from plastoquinol ...

; formate dehydrogenase, respiratory nitrate reductase; succinate - coenzyme Q reductase (fumarate reductase); and

succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...

. See

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples ...

. * Cytochrome c oxidases from

and

Electrochemical potential-driven transporters

*Proton or sodium translocating F-type and V-type ATPases

P-P-bond hydrolysis-driven transporters

*P-type calcium ATPase (five different conformations) *Calcium ATPase regulators phospholamban and sarcolipin * ABC transporters *General secretory pathway (Sec) translocon (preprotein translocase SecY)

Porters (uniporters, symporters, antiporters)

* Mitochondrial carrier proteins *Major Facilitator Superfamily (Glycerol-3-phosphate transporter, Lactose permease, and Multidrug transporter EmrD) * Resistance-nodulation-cell division (multidrug efflux transporter AcrB, see multidrug resistance) *Dicarboxylate/amino acid:cation symporter (proton glutamate symporter) *Monovalent cation/proton antiporter (Sodium/proton antiporter 1 NhaA) *

Neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

sodium symporter *Ammonia transporters *Drug/Metabolite Transporter (small multidrug resistance transporter EmrE - the structures are retracted as erroneous)

Alpha-helical channels including ion channels

* Voltage-gated ion channel like, including potassium channels KcsA and KvAP, and inward-rectifier potassium ion channel Kirbac * Large-conductance mechanosensitive channel, MscL * Small-conductance mechanosensitive ion channel (MscS) * CorA metal ion transporters * Ligand-gated ion channel of

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

receptors ( acetylcholine receptor) *

Aquaporin Aquaporins, also called water channels, are channel proteins from a larger family of major intrinsic proteins that form pores in the membrane of biological cells, mainly facilitating transport of water between cells. The cell membranes of a ...

s * Chloride channels *Outer membrane auxiliary proteins (polysaccharide transporter) - α-helical transmembrane proteins from the outer bacterial membrane

Enzymes

* Methane monooxygenase *

Rhomboid protease The rhomboid proteases are a family of enzymes that exist in almost all species. They are proteases: they cut the polypeptide chain of other proteins. This proteolytic cleavage is irreversible in cells, and an important type of cellular regulation ...

* Disulfide bond formation protein (DsbA-DsbB complex)

Proteins with alpha-helical transmembrane anchors

T cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding ...

transmembrane dimerization domain ] *Cytochrome c nitrite reductase complex *Steryl-sulfate sulfohydrolase *Stannin * Glycophorin A dimer *Inovirus ( filamentous phage) major coat protein * Pilin *

Pulmonary surfactant Pulmonary surfactant is a surface-active complex of phospholipids and proteins formed by type II alveolar cells. The proteins and lipids that make up the surfactant have both hydrophilic and hydrophobic regions. By adsorbing to the air-water in ...

-associated protein * Monoamine oxidases A and B * Fatty acid amide hydrolase * Cytochrome P450 oxidases * Corticosteroid 11β-dehydrogenases . * Signal Peptide Peptidase *Membrane protease specific for a stomatin homolog

Beta-barrels composed of a single polypeptide chain

*Beta barrels from eight beta-strands and with "shear number" of ten (''n=8, S=10''). They include: **

OmpA-like transmembrane domain OmpA-like transmembrane domain is an evolutionarily conserved domain of bacterial outer membrane proteins. This domain consists of an eight-stranded beta barrel. OmpA is the predominant cell surface antigen in enterobacteria found in about 100,00 ...

(OmpA) **

Virulence-related outer membrane protein family Virulence-related outer membrane proteins, or outer surface proteins (Osp) in some contexts, are expressed in the outer membrane of gram-negative bacteria and are essential to bacterial survival within macrophages and for eukaryotic cell invasion ...

(OmpX) **

Outer membrane protein W family Outer membrane protein W (OmpW) family is a family of evolutionarily related proteins from the bacterial outer membrane. This family includes outer membrane protein W (OmpW) proteins from a variety of bacterial species. This protein may form the ...

(OmpW) ** Antimicrobial peptide resistance and lipid A acylation protein family (PagP) ** Lipid A deacylase PagL ** Opacity family porins (NspA) *

Autotransporter domain In molecular biology, an autotransporter domain is a structural domain found in some bacterial outer membrane proteins. The domain is always located at the C-terminal end of the protein and forms a beta-barrel structure. The barrel is oriented in ...

(''n=12,S=14'') *

FadL outer membrane protein transport family Outer membrane transport proteins (OMPP1/FadL/TodX) family includes several proteins that are involved in toluene catabolism and degradation of aromatic hydrocarbons. This family also includes protein FadL involved in translocation of long-chain ...

, including

Fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

transporter FadL (''n=14,S=14'') * General bacterial porin family, known as trimeric porins (''n=16,S=20'') *

Maltoporin Maltoporins (or LamB porins) are bacterial outer membrane proteins of the porin (protein), porin protein family, family. Maltoporin forms a trimeric structure which facilitates the diffusion of maltodextrins across the outer membrane of Gram-negat ...

, or sugar porins (''n=18,S=22'') * Nucleoside-specific porin (''n=12,S=16'') * Outer membrane phospholipase A1(''n=12,S=16'') *

TonB-dependent receptors Outer membrane receptors, also known as TonB-dependent receptors, are a family of beta barrel proteins named for their localization in the outer membrane of gram-negative bacteria. TonB complexes sense signals from the outside of bacterial cells ...

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 *

Outer membrane protein OpcA Outer membrane adhesin OpcA protein family consists of several Neisseria species specific outer membrane proteins. ''Neisseria meningitidis'' causes meningococcal meningitis and sepsis. Opc (formerly called 5C) is one of the major outer membrane ...

family (''n=10,S=12'') that includes outer membrane

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

OmpT and adhesin/invasin OpcA protein * Outer membrane protein G porin family (''n=14,S=16'') Note: ''n'' and ''S'' are, respectively, the number of beta-strands and the "shear number" of the beta-barrel

Beta-barrels composed of several polypeptide chains

* Trimeric autotransporter (''n=12,S=12'') *

Outer membrane efflux proteins Proteins in the outer membrane efflux protein family form trimeric (three-piece) channels that allow export of a variety of substrates in gram-negative bacteria. Each member of this family is composed of two repeats. The trimeric channel is compo ...

, also known as trimeric outer membrane factors (n=12,S=18) including TolC and multidrug resistance proteins *

MspA porin Mycobacterial porins are a group of transmembrane beta-barrel proteins produced by mycobacteria, which allow hydrophilic nutrients to enter the bacterium.Membrane protein * Membrane topology * Transmembrane domain * Transmembrane receptors

References

{{DEFAULTSORT:Transmembrane Protein Integral membrane proteins