Abstract
SummaryTail-anchored (TA) proteins, defined by the presence of a single C-terminal transmembrane domain (TMD), play critical roles throughout the secretory pathway and in mitochondria, yet the machinery responsible for their proper membrane insertion remains poorly characterized. Here we show that Get3, the yeast homolog of the TA-interacting factor Asna1/Trc40, specifically recognizes TMDs of TA proteins destined for the secretory pathway. Get3 recognition represents a key decision step, whose loss can lead to misinsertion of TA proteins into mitochondria. Get3-TA protein complexes are recruited for endoplasmic reticulum (ER) membrane insertion by the Get1/Get2 receptor. In vivo, the absence of Get1/Get2 leads to cytosolic aggregation of Get3-TA complexes and broad defects in TA protein biogenesis. In vitro reconstitution demonstrates that the Get proteins directly mediate insertion of newly synthesized TA proteins into ER membranes. Thus, the GET complex represents a critical mechanism for ensuring efficient and accurate targeting of TA proteins.
Highlights
The biogenesis of transmembrane proteins presents the cell with several compounding challenges
Far less is known about the machinery responsible for the insertion of an important class of proteins that are anchored to the lipid bilayer by a single transmembrane domains (TMDs) located near their C termini
Earlier studies established that Get3, which, unlike Get1 and Get2, is not predicted to have TMDs, is found on the surface of the endoplasmic reticulum (ER) as well as in the cytosol
Summary
The biogenesis of transmembrane proteins presents the cell with several compounding challenges. Proteins containing TMDs must find their correct target membrane for insertion among the different membrane-surrounded compartments present in eukaryotic cells To face these challenges, cells have evolved diverse mechanisms for chaperoning membrane proteins, often from the earliest stages of their biosynthesis on the ribosome to their proper destinations. Far less is known about the machinery responsible for the insertion of an important class of proteins that are anchored to the lipid bilayer by a single TMD located near their C termini This topological arrangement allows tail-anchored (TA) proteins to be tethered to internal membranes while presenting their functional N-terminal domains to the cytosol (Borgese et al, 2007; Wattenberg and Lithgow, 2001). It is not well understood how targeting determinants in the TMDs are decoded by cellular machinery (Borgese et al, 2007)
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