( c) Three-dimensional structure of bovine rhodopsin showing that TMDs are highly variable in structure some are tilted or kinked. Sequences of the first and last TMDs are shown polar residues within each TMD are indicated by asterisks. Note that six of the seven transmembrane domains (TMDs) are easily recognizable by their hydrophobicity, but the seventh is more polar. The hydrophobic regions are below the axis and indicated in gold. ( b) Hydrophilicity plot of a G protein–coupled receptor (bovine rhodopsin) using the Kyte-Doolittle scale. Most types of membrane proteins are inserted by a cotranslational pathway, although some use a posttranslational pathway. ( a) Several types of integral membrane proteins are shown in different topologies. The structural diversity of integral membrane proteins. Otherwise, one of several quality-control pathways routes the IMP for degradation ( Hegde & Ploegh 2010, Meusser et al. If these decisive steps in IMP biogenesis are successful, the IMP is subsequently sorted to its final location of function ( Pryer et al. This is the site where an IMP’s TMD(s) are integrated into the membrane, final topology is determined, and tertiary and quaternary structures are achieved ( Alder & Johnson 2004, Rapoport et al. All these proteins are initially assembled at the endoplasmic reticulum (ER). Most of the cell’s IMPs populate the plasma membrane and intracellular compartments of the secretory and endocytic pathways. Structurally, IMPs range from having a single transmembrane domain (TMD) that simply anchors a soluble domain to the membrane to having tightly packed bundles containing more than 20 TMDs ( Figure 1 a). They serve many essential cellular functions, such as functioning as signaling receptors, mediating intracellular trafficking, facilitating organelle biogenesis, and transporting a variety of molecules across cellular membranes. Integral membrane proteins (IMPs) make up 20–30% of the eukaryotic proteome and are extremely diverse. Here, we review the conceptual and mechanistic themes underlying these core membrane protein insertion pathways, the complexities that challenge our understanding, and future directions to over-come these obstacles. Both of these pathways overcome the same biophysical challenges of ferrying hydrophobic cargo through an aqueous milieu, selectively delivering it to one among several intracellular membranes and asymmetrically integrating its transmembrane domain(s) into the lipid bilayer. A more specialized posttranslational pathway, employed by many tail-anchored membrane proteins, is composed of entirely different factors centered around a cytosolic ATPase termed TRC40 or Get3. The classical cotranslational pathway, utilized by most membrane proteins, involves targeting by the signal recognition particle followed by insertion via the Sec61 translocon. Two highly conserved and parallel pathways mediate membrane protein targeting to and insertion into this organelle. Integral membrane proteins of the cell surface and most intracellular compartments of eukaryotic cells are assembled at the endoplasmic reticulum.
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