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Tail-Anchored Proteins
Insertion of proteins into biological membranes is a fundamental process vital to all organisms. Although most membrane proteins utilize the classical co-translational translocation pathway (left side of Figure), many utilize poorly understood post-translational membrane insertion pathways (right side of Figure). The main clients for these pathways are tail anchored (TA) membrane proteins defined by a cytosolic-facing N-terminal domain followed by a single C-terminal transmembrane domain (TMD). Examples of TA proteins are found on essentially all cellular membranes in every organism and have diverse functional roles ranging from intracellular trafficking to regulation of cell death. Despite this widespread importance, the machinery and mechanisms underlying the recognition, targeting, and insertion of TA proteins into the correct organellar membrane remain largely unknown. Recently, we discovered a cytosolic TMD recognition complex (TRC) that selectively interacts with TA proteins destined for the ER membrane. A central component of TRC was identified as a highly conserved 40 kD ATPase and represents the first molecular factor in this widely used membrane protein insertion pathway. We are now taking various approaches to identify these additional factor(s) and reconstitute the targeting reaction for TA proteins with defined components. Achieving these goals will define the core machinery and functions for a fundamental protein trafficking pathway and pave the way for future mechanistic and structural analyses.
