Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control

Martínez-Lumbreras, Santiago and Krysztofinska, Ewelina M. and Thapaliya, Arjun and Spilotros, Alessandro and Matak-Vinkovic, Dijana and Salvadori, Enrico and Roboti, Peristera and Nyathi, Yvonne and Muench, Janina H. and Roessler, Maxie M. and Svergun, Dmitri I. and High, Stephen and Isaacson, Rivka L. (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). ISSN 1741-7007

Full content URL: http://doi.org/10.1186/s12915-018-0542-3

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Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control
https://doi.org/10.1186/s12915-018-0542-
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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 C-terminal 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. Results 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. Conclusion 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.

Keywords:Protein Misfolding – Protein Quality Control – Chaperones – Ubiquitination – Protein Translocation – Protein Energy Landscapes – Proteotoxicity – Unfolded Protein Response – ER Associated Degradation – Membrane targeting – Autophagy – Co-Translational Fol
Subjects:C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science > School of Life Sciences
ID Code:32657
Deposited On:16 Jul 2018 10:42

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