Piccolo, also known as Aczonin, is a multidomain zinc finger protein found in the cytomatrix of vertebrate presynaptic terminals. Human Piccolo is 5065 amino acids (aa) in length and has a predicted molecular weight of approximately 553 kDa. It contains N-terminal Pro- and Gln-rich sequences and two C4-type zinc-finger domains (aa 535-559 and 1005-1028). It also has a C-terminal PDZ domain (aa 4427-4478) and two C-terminal C2 domains termed C2A (aa 4565-4669) and C2B (aa 4934-5039). C2A domain has a calcium binding site that is regulated by alternative splicing. Binding to calcium causes this domain to undergo a conformational change and dimerize. On the other hand, the C2B domain does not bind to calcium. Human Piccolo shares 80% aa sequence identity with the mouse and rat orthologs. Multiple splice variants exist due to various aa insertions and deletions. Piccolo acts as a scaffolding protein involved in establishing active synaptic zones and synaptic vesicle trafficking. It is known to be initially present in the trans-Golgi of neuronal cells. When needed, it is transported to the presynaptic density of GABAergic and glutamergic neurons, or to the plasma membrane of pancreatic beta cells, where it forms homodimers and heterodimers with Rim2 and subsequently serves as a calcium sensor for exocytosis.