User:Db03d/sandbox/Wiki Assignment

Transmembrane Domain
Original

Transmembrane domain usually denotes a transmembrane segment of single alpha helix of a transmembrane protein. More broadly, a transmembrane domain is any membrane-spanning protein domain.

Proposed additions below

Integral membrane proteins account for 20–30% of protein-coding genes and play critical roles in cellular functions such as signal transduction, molecular transport, and cell adhesion. The transmembrane domain (TMD) is made up mostly of hydrophobic amino acids and spans the cellular or organelle membrane, generally adopting an alpha helix topological conformation. TMDs vary greatly in length, sequence, and hydrophobicity, adopting organelle-specific properties.

The role of membrane protein biogenesis and quality control factors
Since protein translation occurs in the cytosol (an aqueous 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 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 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 are two well-known general TMD-binding factors. Quality control of membrane proteins involve TMD-binding factors that are linked to ubiquitination proteasome system.

Membrane Recognition Factors
Once transported, factors assist with insertion of the TMD across the hydrophilic 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 central pore and minimizing exposure of the TMD to cytosol. Insertases can also mediate TMD insertion into the lipid bilayer. Insertases include the bacterial YidC, mitochondrial Oxa1, and chloroplast Alb3, all of which are evolutionarily related. The conserved Hrd1 and Derlin enzyme families are examples of membrane bound quality control factors.