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dc.contributor.authorMartínez-Lumbreras, S.
dc.contributor.authorKrysztofinska, E.M.
dc.contributor.authorThapaliya, A.
dc.contributor.authorSpilotros, A.
dc.contributor.authorMatak-Vinkovic, D.
dc.contributor.authorSalvadori, E.
dc.contributor.authorRoboti, P.
dc.contributor.authorNyathi, Yvonne
dc.contributor.authorMuench, J.H.
dc.contributor.authorRoessler, M.M.
dc.contributor.authorSvergun, D.I.
dc.contributor.authorHigh, S.
dc.contributor.authorIsaacson, R.L.
dc.date.accessioned2020-06-08T01:48:44Z
dc.date.accessioned2020-07-01T07:00:54Z
dc.date.available2020-06-08T01:48:44Z
dc.date.available2020-07-01T07:00:54Z
dc.date.issued2018-07-11
dc.identifier.citationMartínez-Lumbreras S, Krysztofinska EM, Thapaliya A et al (2018) Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control. BMC Biology. 16(1): 76.en_US
dc.identifier.urihttp://hdl.handle.net/10454/17888
dc.descriptionYesen_US
dc.description.abstractProtein quality control mechanisms are essential for cell health and involve delivery of proteins to specific cellular compartments for recycling or degradation. In particular, stray hydrophobic proteins are captured in the aqueous cytosol by a co-chaperone, the small glutamine-rich, tetratricopeptide repeat-containing protein alpha (SGTA), which facilitates the correct targeting of tail-anchored membrane proteins, as well as the sorting of membrane and secretory proteins that mislocalize to the cytosol and endoplasmic reticulum-associated degradation. Full-length SGTA has an unusual elongated dimeric structure that has, until now, evaded detailed structural analysis. The Cterminal region of SGTA plays a key role in binding a broad range of hydrophobic substrates, yet in contrast to the well-characterized N-terminal and TPR domains, there is a lack of structural information on the C-terminal domain. In this study, we present new insights into the conformation and organization of distinct domains of SGTA and show that the C-terminal domain possesses a conserved region essential for substrate processing in vivo. We show that the C-terminal domain region is characterized by α-helical propensity and an intrinsic ability to dimerize independently of the N-terminal domain. Based on the properties of different regions of SGTA that are revealed using cell biology, NMR, SAXS, Native MS, and EPR, we observe that its C-terminal domain can dimerize in the full-length protein and propose that this reflects a closed conformation of the substrate-binding domain. Our results provide novel insights into the structural complexity of SGTA and provide a new basis for mechanistic studies of substrate binding and release at the C-terminal region.en_US
dc.description.sponsorshipMRC New Investigator Research Grant: G0900936; BBSRC grants: BB/L006952/1 and BB/L006510/1; BBSRC grant: BB/N006267/1; Wellcome Trust Investigator Award in Science: 204957/Z/16/Z; BBSRC grant: BB/J014567/1en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1186/s12915-018-0542-3en_US
dc.rights(c) 2018 The Authors. This is an Open Access article distributed under the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/)en_US
dc.subjectHydrophobic substratesen_US
dc.subjectEndoplasmic reticulum-associated degradationen_US
dc.subjectProtein quality control mechanismsen_US
dc.subjectBCL2-associated athanogene (BAG6)en_US
dc.subjectDouble electron-electron resonance (DEER)en_US
dc.titleStructural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality controlen_US
dc.status.refereedYesen_US
dc.date.Accepted2018-06-20
dc.typeArticleen_US
dc.type.versionPublished versionen_US
dc.date.updated2020-06-08T00:48:53Z
refterms.dateFOA2020-07-01T07:01:28Z


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