Phosphorylation of Cysteine string protein triggers a major conformational switch
Abstract
Cysteine string protein (CSP) is a member of the DnaJ/Hsp40 chaperone family that localizes to neuronal synaptic vesicles. Impaired CSP function leads to neurodegeneration in humans and model organisms as a result of misfolding of client proteins involved in neurotransmission. Mammalian CSP is phosphorylated in vivo on Ser10, and this modulates its protein interactions and effects on neurotransmitter release. However, there are no data on the structural consequences of CSP phosphorylation to explain these functional effects. We show that Ser10 phosphorylation causes an order-to-disorder transition that disrupts CSP's extreme N-terminal α helix. This triggers the concomitant formation of a hairpin loop stabilized by ionic interactions between phosphoSer10 and the highly conserved J-domain residue, Lys58. These phosphorylation-induced effects result in significant changes to CSP conformation and surface charge distribution. The phospho-switch revealed here provides structural insight into how Ser10 phosphorylation modulates CSP function and also has potential implications for other DnaJ phosphoproteins.
Citation
Patel , P , Prescott , G R , Burgoyne , R D , Lian , L-Y & Morgan , A 2016 , ' Phosphorylation of Cysteine string protein triggers a major conformational switch ' , Structure , vol. 24 , no. 8 , pp. 1380-1386 . https://doi.org/10.1016/j.str.2016.06.009
Publication
Structure
Status
Peer reviewed
ISSN
0969-2126Type
Journal article
Rights
© 2016 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Description
This work was supported by a grant from the Wellcome Trust to A.M., L.Y.L., and R.D.B. (grant ref. 090077/Z/09/Z). G.R.P. was supported by a Wellcome Trust PhD studentship.Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.