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Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control
Martínez-Lumbreras, S. Krysztofinska, E.M. Thapaliya, A. Spilotros, A. Matak-Vinkovic, D. Salvadori, E. Roboti, P. Nyathi, Yvonne Muench, J.H. Roessler, M.M.
Martínez-Lumbreras, S.
Krysztofinska, E.M.
Thapaliya, A.
Spilotros, A.
Matak-Vinkovic, D.
Salvadori, E.
Roboti, P.
Nyathi, Yvonne
Muench, J.H.
Roessler, M.M.
Publication Date
2018-07-11
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(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/)
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2018-06-20
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Abstract
Protein 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.
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Martínez-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.
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