Cysteine-string protein: The chaperone at the synapse

Cysteine-string protein (Csp) is a major synaptic vesicle and secretory gra nule protein first discovered in Drosophila and Torpedo. Csps were subseque ntly identified from Xenopus, Caenorhabditis elegans, and mammalian species . It is clear from the study of a null mutant in Drosophila that Csp is req uired for viability of the organism and that it has a key role in neurotran smitter release. In addition, other studies have directly implicated Csp in regulated exocytosis in mammalian neuroendocrine and endocrine cell types, and its distribution suggests a general role in regulated exocytosis. An e arly hypothesis was that Csp functioned in the control of voltage-gated Ca2 + channels. Csp, however, must have an additional function as a direct regu lator of the exocytotic machinery as changes in Csp expression modify the e xtent of exocytosis triggered directly by Ca2+ in permeabilised cells. Csps possess a cysteine-string domain that is highly palmitoylated and confers membrane targeting. In addition, Csps have a conserved "J" domain that medi ates binding to an activation of the Hsp70/Hsc70 chaperone ATPases. This an d other evidence implicate Csps as molecular chaperones in the synapse that are likely to control the correct conformational folding of one or more co mponents of the vesicular exocytotic machinery. Targets for Csp include the vesicle protein VAMP/synaptobrevin and the plasma membrane protein syntaxi n 1, the significance of which is discussed in possible models to account f or current knowledge of Csp function.