A charged prominence in the linker domain of the cysteine‐string protein Cspα mediates its regulated interaction with the calcium sensor synaptotagmin 9 during exocytosis

  title={A charged prominence in the linker domain of the cysteine‐string protein Csp$\alpha$ mediates its regulated interaction with the calcium sensor synaptotagmin 9 during exocytosis},
  author={Fr{\'e}d{\'e}ric Boal and Michel S. Laguerre and Alexandra Milochau and Jochen Lang and Pier A. Scotti},
  journal={The FASEB Journal},
  pages={132 - 143}
The cochaperone cysteine‐string protein (Csp) is located on vesicles and participates in the control of neurotransmission and hormone exocytosis. Csp contains several domains, and our previous work demonstrated the requirement of the Csp linker domain in regulated exocytosis of insulin in rodent pancreatic β cells. We now address the molecular details to gain insight into the sequence of events during exocy‐tosis. According to pulldown experiments and in vitro binding assays, Cspα interacts… 
Phosphomimetic Mutation of Cysteine String Protein-α Increases the Rate of Regulated Exocytosis by Modulating Fusion Pore Dynamics in PC12 Cells
CSPα may have a great capacity to modulate the rate of regulated exocytosis through changing its phosphorylated state influenced by diverse cellular signalings, and advanced kinetic analysis suggests that overexpression of S10D or S10E may stabilize open fusion pores mainly by inhibiting them from closing.
A Central Small Amino Acid in the VAMP2 Transmembrane Domain Regulates the Fusion Pore in Exocytosis
It is concluded that the TMD of VAMP2 plays a critical role in membrane fusion and that the structural mobility provided by the central small amino acids is crucial for exocytosis by influencing the molecular re-arrangements of the lipid membrane that are necessary for fusion pore opening and expansion.
Neurons Export Extracellular Vesicles Enriched in Cysteine String Protein and Misfolded Protein Cargo
The results indicate that by assisting local lysosome/proteasome processes, CSPα-mediated removal of toxic proteins via EVs plays a central role in synaptic proteostasis and CSP α thus represents a potential therapeutic target for neurodegenerative diseases.
Cysteine string proteins
Identification of CSPa Clients Reveals aR ole in Dynamin 1R egulation
Using hippocampal cultures, it is shown that CSPa regulates the stability of client proteins and synaptic vesicle number, and unexpectedly that C SPa regulating the polymerization of dynamin 1, therefore, participates in synapticvesicle endocytosis and may facilitate exo- and endocytic coupling.
The Role of Cysteine String Protein α Phosphorylation at Serine 10 and 34 by Protein Kinase Cγ for Presynaptic Maintenance
Cysteine string protein α (CSPα) is a protein belonging to the heat shock protein (HSP) 40 cochaperone families localized on synaptic vesicles, which maintain the presynaptic terminal, and may provide a new therapeutic target for the treatment of PD.


Mutational analysis of cysteine-string protein function in insulin exocytosis.
A functional difference between the two isoforms of Csp wild-type or mutants is demonstrated and a role for the J-domain co-chaperone function as well as for the newly defined linker region in LDCV exocytosis is suggested.
Interaction of Cysteine String Proteins with the α1A Subunit of the P/Q-type Calcium Channel*
Cysteine string proteins (Csps) are J-domain chaperone proteins anchored at the surface of synaptic vesicles. Csps are involved in neurotransmitter release and may modulate presynaptic calcium
The variable C-terminus of cysteine string proteins modulates exocytosis and protein-protein interactions.
The data suggest that both interactions of Csp occur during exocytosis and may explain the effect of the variant C-terminus of this chaperon protein on peptide hormone secretion.
The Molecular Chaperone Function of the Secretory Vesicle Cysteine String Proteins*
Results show that both Csp1 and Csp2 can bind a partially unfolded protein and act as chaperones, suggesting that Csps may have a general chaperone function in regulated exocytosis.
Cysteine‐String Protein
Evidence implicate Csps as molecular chaperones in the synapse that are likely to control the correct conformational folding of one or more components of the vesicular exocytotic machinery.
Distinct roles of the C2A and the C2B domain of the vesicular Ca2+ sensor synaptotagmin 9 in endocrine beta-cells.
Different intracellular properties of syt9 with different roles for each C2 domain in endocrine cells are demonstrated, including calcium-dependent membrane binding and post-stimulatory localization to endosomes.
Tying Everything Together: The Multiple Roles of Cysteine String Protein (CSP) in Regulated Exocytosis
Recent experiments that associate cysteine string protein with the regulation of vesicle filling, vesicles docking, Ca2+‐channels and the SNARE proteins themselves are summarized, supporting a role for cysteined string protein as a multifunctional secretory co‐chaperone.
The Cysteine String Secretory Vesicle Protein Activates Hsc70 ATPase*
The results suggest that CSP, a DnaJ family member associated with the secretory vesicle cycle regulates Hsc70 functions, which may function within the biochemical pathways of exo- and endocytosis to promote the formation of multimeric complexes or to regulate conformational changes.
Phosphorylation-dependent interaction of the synaptic vesicle proteins cysteine string protein and synaptotagmin I.
Binding assays in vitro using recombinant proteins confirmed a direct interaction between the two proteins and demonstrated that the PKA-phosphorylated form of CSP binds synaptotagmin with approximately an order of magnitude lower affinity than the non-ph phosphate-based form.