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Phosphorylation of Cysteine string protein triggers a major conformational switch

Research output: Contribution to journalArticlepeer-review

Author(s)

Pryank Patel, Gerald R. Prescott, Robert D. Burgoyne, Lu-Yun Lian, Alan Morgan

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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.

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Details

Original languageEnglish
Pages (from-to)1380-1386
Number of pages7
JournalStructure
Volume24
Issue number8
Early online date21 Jul 2016
DOIs
Publication statusPublished - 2 Aug 2016

    Research areas

  • Adult onset neuronal lipofuscinosis, Chaperone, DnaJ, Hsp40, Neurodegeneration

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