A transmembrane protein (TP) is a type of
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...
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 (the ...
. 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 and aggregate and precipitate in water. They require
detergent
A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are m ...
s 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 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
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...
,
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 and
chloroplasts
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it i ...
, 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 pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
. 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). 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.
3D structure
Membrane protein structures can be determined by
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...
,
electron microscopy or
NMR spectroscopy. 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 struct ...
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 alpha-helical (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
A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are m ...
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 (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transport ...
. 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
Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransduct ...
(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 pro ...
)
*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. Photos ...
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
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it i ...
Oxidoreduction-driven transporters
*Transmembrane cytochrome b-like proteins:
coenzyme Q - cytochrome c reductase (cytochrome bc1 );
cytochrome b6f complex; formate dehydrogenase, respiratory
nitrate reductase;
succinate - coenzyme Q reductase
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 ...
(fumarate reductase); and
succinate dehydrogenase. 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 couple ...
.
*
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory el ...
s 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
mitochondria
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 The translocon (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transport ...
(preprotein translocase SecY)
Porters (uniporters, symporters, antiporters)
*
Mitochondrial
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 us ...
carrier proteins
*Major Facilitator Superfamily (Glycerol-3-phosphate transporter, Lactose
permease, and Multidrug transporter EmrD)
*
Resistance-nodulation-cell division (multidrug
efflux
Efflux may refer to:
* Efflux (microbiology), a mechanism responsible for moving compounds out of cells
* e-flux, a publishing platform and archive
See also
* Efflux time, part of a measure of paint viscosity
* Flux (biology)
In general, flux ...
transporter AcrB, see
multidrug resistance
Multiple drug resistance (MDR), multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Antimicrobial categories a ...
)
*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.
Neur ...
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
The Large Conductance Mechanosensitive Ion Channel (MscL) FamilyTC# 1.A.22 consists of pore-forming membrane proteins that are responsible for translating physical forces applied to cell membranes into electrophysiological activities. MscL has a ...
*
Small-conductance mechanosensitive ion channel (MscS)
*
CorA metal ion transporters
*
Ligand-gated ion channel
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in re ...
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.
Neur ...
receptors (
acetylcholine receptor)
*
Aquaporins
*
Chloride channels
*Outer membrane auxiliary proteins (polysaccharide transporter) - α-helical transmembrane proteins from the outer bacterial membrane
Enzymes
*
Methane monooxygenase
*
Rhomboid protease
*
Disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups ...
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 bindin ...
transmembrane dimerization domain ]
*Cytochrome c
nitrite reductase complex
*Steryl-sulfate sulfohydrolase
*Stannin
*
Glycophorin A dimer
*Inovirus (
filamentous phage) major coat protein
*
Pilin
*
Pulmonary surfactant-associated protein
*
Monoamine oxidases A and B
*
Fatty acid amide hydrolase
*
Cytochrome P450 oxidase
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various ...
s
*
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)
**
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)
**
(PagP)
**
Lipid A deacylase PagL
Lipid A deacylase (PagL) is an outer membrane protein with lipid A
Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LP ...
**
Opacity family porins
Opacity family porins are a family of porin (protein), porins from pathogenic ''Neisseria''.
These bacteria possess a repertoire of phase-variable opacity proteins that mediate various pathogen/host cell interactions. These proteins are related t ...
(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 oriente ...
(''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, ...
transporter FadL (''n=14,S=14'')
*
General bacterial porin family, known as trimeric
porins (''n=16,S=20'')
*
Maltoporin, or sugar
porins (''n=18,S=22'')
*
Nucleoside-specific porin
Nucleoside-specific porin (the tsx gene of ''Escherichia coli'') is an outer membrane protein, Tsx, which constitutes the receptor for colicin K and '' Bacteriophage T6'', and functions as a substrate-specific channel for nucleosides
Nucleosid ...
(''n=12,S=16'')
*
Outer membrane phospholipase A1(''n=12,S=16'')
*
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
*
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 membran ...
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 form ...
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 (octamer, ''n=S=16'') and α-hemolysin (heptamer ''n=S=14'') . These proteins are secreted.
See also
*
Membrane protein
*
Membrane topology
*
Transmembrane domain
*
Transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...
s
References
{{DEFAULTSORT:Transmembrane Protein
Integral membrane proteins