Abstract: Nothing in nature is as intricately designed as the synapse. Within the synapse lie two perfectly aligned areas of specialization that aid the transfer of information from cell to cell, the cytomatrix at the active zone (CAZ), at the presynaptic membrane, and the postsynaptic density (PSD), at the postsynaptic membrane. We have shown that a master scaffolding protein located in the heart of the PSD, Shank, forms massive sheets through the self-association of its sterile alpha motif (SAM) domain. Furthermore, Zn2+ binds directly to Shank-SAM and increases the order of the Shank-SAM sheets. Shank may therefore serve as a platform for assembly of the myriad of proteins that make up the PSD, providing a higher order organization to this vast and complex network. We next analyzed all known SAM domain sequences (over 1,400) for the ability the bind Zn2+ and found that over half of them contained potential Zn2+ binding residues in the same site as Shank-SAM. By experimentally testing a subset of these, we found that many diverse SAM domains are able to bind Zn2+ (Byr2-SAM, DGK-SAM, SCM-SAM, Ste4-SAM, TEL-SAM and Liprin-SAM2), but not all (Ph-SAM). Moreover, Zn2+ was demonstrated to cause ordering of these SAM domains into various structures including sheets reminiscent of Shank-SAM (DGK-SAM), polymers (SCM-SAM), and uniform closed oligomers (Ste4-SAM). Thus Zn2+, through its action on SAM domains, may facilitate a sizable array of biological processes, including synaptic organization, neuronal patterning, chromosomal repression, and sexual differentiation. Lastly, we have conducted a preliminary investigation of one CAZ localized protein (Liprin) that has the unique feature of containing three tandem SAM domains. We have found that the three SAM domains of Liprin are able to form an extremely robust sheet-like structure that resembles those previously seen (Shank-SAM and DGK-SAM). It may be that Liprin's three SAM domains are able to provide structure to the CAZ through self-association as Shank-SAM does in the PSD. Overall, these results highlight a new executive role for SAM domains in synaptic organization which is enhanced through their interaction with Zn2+.