Phosphorylation of Cysteine String Protein Triggers a Major Conformational Switch

Patel, Pryank, Prescott, Gerald R, Burgoyne, Robert D ORCID: 0000-0002-9219-0387, Lian, Lu-Yun and Morgan, Alan ORCID: 0000-0002-0346-1289 (2016) Phosphorylation of Cysteine String Protein Triggers a Major Conformational Switch. STRUCTURE, 24 (8). pp. 1380-1386.

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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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Escherichia coli, Lysine, Serine, Escherichia coli Proteins, Membrane Proteins, Recombinant Proteins, Nuclear Magnetic Resonance, Biomolecular, Cloning, Molecular, Gene Expression, Binding Sites, Amino Acid Motifs, Protein Structure, Tertiary, Structural Homology, Protein, Protein Binding, Phosphorylation, Kinetics, Thermodynamics, Models, Molecular, HSC70 Heat-Shock Proteins, HSP40 Heat-Shock Proteins, Protein Interaction Domains and Motifs, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand
Depositing User:	Symplectic Admin
Date Deposited:	03 Aug 2016 14:42
Last Modified:	19 Jan 2023 07:32
DOI:	10.1016/j.str.2016.06.009
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3002738