A transmembrane domain (TMD) is a membrane-spanning
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of ...
. TMDs generally adopt an
alpha helix topological conformation, although some TMDs such as those in
porins
Porins are beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse. Unlike other membrane transport proteins, porins are large enough to allow passive diffusion, i.e., they act as channels tha ...
can adopt a different conformation. Because the interior of the lipid bilayer is
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, t ...
, the amino acid residues in TMDs are often hydrophobic, although proteins such as
membrane pumps and
ion channels can contain polar residues. TMDs vary greatly in length,
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
, and
hydrophobicity
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, t ...
, adopting organelle-specific properties.
Functions of transmembrane domains
Transmembrane domains are known to perform a variety of functions. These include:
* Anchoring
transmembrane protein
A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
s to the membrane.
![AMPA receptor(cropped)](https://upload.wikimedia.org/wikipedia/commons/9/9d/AMPA_receptor%28cropped%29.png)
*Facilitating molecular transport of molecules such as
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s and
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s across
biological membranes; usually hydrophilic residues and binding sites in the TMDs help in this process.
*
Signal transduction across the membrane; many transmembrane proteins, such as
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, receive extracellular signals. TMDs then propagate those signals across the membrane to induce an intracellular effect.
* Assisting in
vesicle fusion Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles c ...
; the function of TMDs is not well understood, but they have been shown to be critical for the fusion reaction, possibly as a result of TMDs affecting the tension of the lipid bilayer.
* Mediating transport and sorting of transmembrane proteins; TMDs have been shown to work in tandem with cytosolic sorting signals, with length and hydrophobicity being the main determinants in TDM sorting. Longer and more hydrophobic TMDs aid in sorting proteins to the cell membrane, whereas shorter and less hydrophobic TMDs are used to retain proteins in the
endoplasmic reticulum and the
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ins ...
. The exact mechanism of this process is still unknown.
Identification of transmembrane helices
Transmembrane helices are visible in structures of membrane proteins determined by
X-ray diffraction. They may also be predicted on the basis of
hydrophobicity scales Hydrophobicity scales are values that define the relative hydrophobicity or hydrophilicity of amino acid residues. The more positive the value, the more hydrophobic are the amino acids located in that region of the protein. These scales are commonly ...
. Because the interior of the
bilayer
A bilayer is a double layer of closely packed atoms or molecules.
The properties of bilayers are often studied in condensed matter physics, particularly in the context of semiconductor devices, where two distinct materials are united to form jun ...
and the interiors of most proteins of known structure are
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, t ...
, it is presumed to be a requirement of the amino acids that span a membrane that they be hydrophobic as well. However,
membrane pump
A diaphragm pump (also known as a Membrane pump) is a positive displacement pump that uses a combination of the reciprocating action of a rubber, thermoplastic or teflon diaphragm and suitable valves on either side of the diaphragm
(check valve, ...
s and
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s also contain numerous charged and polar residues within the generally non-polar transmembrane segments.
Using
"hydrophobicity analysis" to predict transmembrane helices enables a prediction in turn of the
"transmembrane topology" of a protein; i.e. prediction of what parts of it protrude into the cell, what parts protrude out, and how many times the protein chain crosses the membrane.
Transmembrane helices can also be identified ''
in silico'' using the
bioinformatic
Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combine ...
tool
TMHMM
The role of membrane protein biogenesis and quality control factors
Since protein
translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
occurs in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
(an
aqueous
An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be re ...
environment), factors that recognize the TMD and protect them in this hostile environment are required. Additional factors that allow the TMD to be incorporated into the target membrane (i.e.
endoplasmic reticulum or other organelles) are also required.
Factors also detect TMD misfolding within the membrane and perform quality control functions. These factors must be able to recognize a highly variable set of TMDs and can be segregated into those active in the cytosol or active in the membrane.
Cytosolic Recognition Factors
Cytosolic recognition factors are thought to use two distinct strategies.
In the co-translational strategy the recognition and shielding are coupled to protein synthesis.
Genome wide association studies indicate the majority of membrane proteins targeting the endoplasmic reticulum are handled by the
signal recognition particle
The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein (protein- RNA complex) that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membr ...
which is bound to the ribosomal exit tunnel and initiates recognition and shielding as protein is translated. The second strategy involves tail-anchored proteins, defined by a single TMD located close to the carboxyl terminus of the membrane protein. Once translation is completed, the tail-anchored TMD remains in the ribosomal exit tunnel, and an ATPase mediates targeting to the endoplasmic reticulum. Examples of shuttling factors include TRC40 in higher eukaryotes and Get3 in yeast. Furthermore, general TMD-binding factors protect against aggregation and other disrupting interactions.
SGTA
Small glutamine-rich tetratricopeptide repeat-containing protein alpha is a protein that in humans is encoded by the ''SGTA'' gene. ''SGTA'' orthologs have also been identified in several mammals for which complete genome data are available.
Fu ...
and
calmodulin are two well-known general TMD-binding factors. Quality control of membrane proteins involve TMD-binding factors that are linked to
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ation
proteasome system.
Membrane Recognition Factors
Once transported, factors assist with insertion of the TMD across the
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are ...
layer phosphate "head" group of the
phospholipid membrane.
Quality control factors must be able to discern function and topology, as well as facilitate extraction to the cytosol. The signal recognition particle transports membrane proteins to the Sec
translocation channel, positioning the ribosome exit tunnel proximal to the
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 ...
central pore and minimizing exposure of the TMD to cytosol. Insertases can also mediate TMD insertion into the
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
. Insertases include the bacterial YidC, mitochondrial Oxa1, and chloroplast Alb3, all of which are
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
arily related. The
conserved Hrd1
E3 ubiquitin-protein ligase synoviolin is an enzyme that in humans is encoded by the ''SYVN1'' gene.
Function
This gene encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The encoded protein removes unfolded protei ...
and
Derlin enzyme families are examples of membrane bound quality control factors.
Examples
*
Tetraspanin
Tetraspanins are a family of membrane proteins found in all multicellular eukaryotes.
Tetraspanins, also referred to as the transmembrane 4 superfamily (TM4SF) proteins, have four transmembrane alpha-helices and two extracellular domains, one s ...
s have 4 conserved transmembrane domains.
*
Mildew locus o (''mlo'') proteins have 7 conserved transmembrane domains that encode alpha helices.
References
{{reflist
Transmembrane proteins
Protein structural motifs