Short Review Cysteine-String Protein: The Chaperone at the Synapse

Abstract: Cysteine-string protein (Csp) is a major syn-aptic vesicle and secretory granule protein first discov-ered in Drosophila and Torpedo. Csps were subsequently identified from Xenopus, Caenorhabditis elegans, and mammalian species. It is clear from the study of a null mutant in Drosophila that Csp is required for viability of the organism and that it has a key role in neurotransmitter release. In addition, other studies have directly implicated Csp in regulated exocytosis in mammalian neuroendo-crine and endocrine cell types, and its distribution sug-gests a general role in regulated exocytosis. An early hypothesis was that Csp functioned in the control of voltage-gated Ca21 channels. Csp, however, must have an additional function as a direct regulator of the exocy-totic machinery as changes in Csp expression modify the extent of exocytosis triggered directly by Ca21 in per-meabilised cells. Csps possess a cysteine-string domain that is highly palmitoylated and confers membrane tar-geting. In addition, Csps have a conserved “J ” domain that mediates binding to an activation of the Hsp70/ Hsc70 chaperone ATPases. This and other evidence im-plicate 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 ma-chinery. Targets for Csp include the vesicle protein VAMP/synaptobrevin and the plasma membrane protein syntaxin 1, the significance of which is discussed in pos-sible models to account for current knowledge of Cs