8odu
Chaetomium thermophilum Get1/Get2 heterotetramer in complex with a Get3 dimer (amphipol)
Structural highlights
FunctionG0SFE0_CHATD ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dimer state, facilitating recognition of newly synthesized TA membrane proteins. ATP hydrolysis is required for insertion. Subsequently, the homodimer reverts towards the open dimer state, lowering its affinity for the membrane-bound receptor, and returning it to the cytosol to initiate a new round of targeting.[HAMAP-Rule:MF_03112] Publication Abstract from PubMedThe eukaryotic guided entry of tail-anchored proteins (GET) pathway mediates the biogenesis of tail-anchored (TA) membrane proteins at the endoplasmic reticulum. In the cytosol, the Get3 chaperone captures the TA protein substrate and delivers it to the Get1/Get2 membrane protein complex (GET insertase), which then inserts the substrate via a membrane-embedded hydrophilic groove. Here, we present structures, atomistic simulations and functional data of human and Chaetomium thermophilum Get1/Get2/Get3. The core fold of the GET insertase is conserved throughout eukaryotes, whilst thinning of the lipid bilayer occurs in the vicinity of the hydrophilic groove to presumably lower the energetic barrier of membrane insertion. We show that the gating interaction between Get2 helix alpha3' and Get3 drives conformational changes in both Get3 and the Get1/Get2 membrane heterotetramer. Thus, we provide a framework to understand the conformational plasticity of the GET insertase and how it remodels its membrane environment to promote substrate insertion. The GET insertase exhibits conformational plasticity and induces membrane thinning.,McDowell MA, Heimes M, Enkavi G, Farkas A, Saar D, Wild K, Schwappach B, Vattulainen I, Sinning I Nat Commun. 2023 Nov 14;14(1):7355. doi: 10.1038/s41467-023-42867-2. PMID:37963916[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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