Transmembrane Domain
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A transmembrane domain (TMD, TM domain) is a membrane-spanning
protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...
. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and
ion channels 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 ...
can contain polar residues. TMDs vary greatly in size and
hydrophobicity In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly intermolecular force, repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to b ...
; they may adopt 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 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 frequently un ...
s to the membrane. *Facilitating molecular transport of molecules such as ions and
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s across
biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of th ...
s; usually hydrophilic residues and binding sites in the TMDs help in this process. *
Signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
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 ...
s, receive extracellular signals. TMDs then propagate those signals across the membrane to induce an intracellular effect. * Assisting in vesicle fusion; 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 The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
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 Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
. 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 X-ray diffraction is a generic term for phenomena associated with changes in the direction of X-ray beams due to interactions with the electrons around atoms. It occurs due to elastic scattering, when there is no change in the energy of the waves. ...
. They may also be predicted on the basis of hydrophobicity scales. Because the interior of the bilayer and the interiors of most proteins of known structure are
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
, it is presumed to be a requirement of the amino acids that span a membrane that they be hydrophobic as well. However, membrane pumps 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 (electrophysiol ...
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 In biology and other experimental sciences, an ''in silico'' experiment is one performed on a computer or via computer simulation software. The phrase is pseudo-Latin for 'in silicon' (correct ), referring to silicon in computer chips. It was c ...
'' using the bioinformatic tool
TMHMM


The role of membrane protein biogenesis and quality control factors

Since protein
translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
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, also known as sodium chloride (NaCl), in wat ...
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 The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
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 membrane ...
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 and
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
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 19 ...
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 n ...
layer phosphate "head" group of the
phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
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 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 form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...
. Insertases include the bacterial YidC, mitochondrial Oxa1, and chloroplast Alb3, all of which are
evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...
arily related. The conserved Hrd1 and Derlin enzyme families are examples of membrane bound quality control factors.


Examples

* Tetraspanins 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