Piccolo is a novel component of the presynaptic cytoskeletal matrix (PCM) a
ssembled at the active zone of neurotransmitter release. Analysis of its pr
imary structure reveals that Piccolo is a multidomain zinc finger protein s
tructurally related to Bassoon, another PCM protein. Both proteins were fou
nd to be shared components of glutamatergic and GABAergic CNS synapses but
not of the cholinergic neuromuscular junction. The Piccolo zinc fingers wer
e found to interact with the dual prenylated rab3A and VAMP2/Synaptobrevin
II receptor PRA1. We show that PRA1 is a synaptic vesicle-associated protei
n that is colocalized with Piccolo in nerve terminals of hippocampal primar
y neurons. These data suggest that Piccolo plays a role in the trafficking
of synaptic vesicles (SVs) at the active zone.