Structural highlights
Function
GET3_HUMAN 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 GET1/WRB and CAMLG/GET2, 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 GET1-CAMLG receptor, and returning it to the cytosol to initiate a new round of targeting. May be involved in insulin signaling.[HAMAP-Rule:MF_03112][1] [2] [3] [4]
Publication Abstract from PubMed
The 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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Stefanovic S, Hegde RS. Identification of a targeting factor for posttranslational membrane protein insertion into the ER. Cell. 2007 Mar 23;128(6):1147-59. PMID:17382883 doi:10.1016/j.cell.2007.01.036
- ↑ Favaloro V, Spasic M, Schwappach B, Dobberstein B. Distinct targeting pathways for the membrane insertion of tail-anchored (TA) proteins. J Cell Sci. 2008 Jun 1;121(11):1832-40. PMID:18477612 doi:10.1242/jcs.020321
- ↑ Yamamoto Y, Sakisaka T. Molecular machinery for insertion of tail-anchored membrane proteins into the endoplasmic reticulum membrane in mammalian cells. Mol Cell. 2012 Nov 9;48(3):387-97. PMID:23041287 doi:10.1016/j.molcel.2012.08.028
- ↑ Mock J, Chartron JW, Zaslaver M, Xu Y, Ye Y, Clemons WM Jr. Bag6 complex contains a minimal tail-anchor-targeting module and a mock BAG domain. Proc Natl Acad Sci U S A. 2014 Dec 22. pii: 201402745. PMID:25535373 doi:http://dx.doi.org/10.1073/pnas.1402745112
- ↑ McDowell MA, Heimes M, Enkavi G, Farkas Á, Saar D, Wild K, Schwappach B, Vattulainen I, Sinning I. The GET insertase exhibits conformational plasticity and induces membrane thinning. Nat Commun. 2023 Nov 14;14(1):7355. PMID:37963916 doi:10.1038/s41467-023-42867-2
