SH3 and multiple ankyrin repeat domains protein 3 (SHANK3)

SHANK3, or SH3 and multiple ankyrin repeat domains protein 3, is a major postsynaptic density scaffold protein central to excitatory synapse organization, dendritic spine formation, and synaptic signaling. The protein contains multiple interaction domains (ANK, SH3, PDZ, PRO, SAM), enabling it to connect neurotransmitter receptors, ion channels, and membrane proteins with the actin cytoskeleton and G-protein signaling pathways. Its genetic deficiency or mutation causes autism spectrum disorders and is associated with Phelan–McDermid syndrome due to deletions at chromosome 22q13.3. SHANK3 also plays roles outside the brain, with emerging evidence of involvement in cardiac muscle and possibly other tissues, mediated by its interactions with actin-regulatory proteins and phospholipase Cβ1b. No current therapeutics directly target SHANK3, but it is a key research focus for neuropsychiatric and developmental disorders.

Other names

Proline-rich synapse-associated protein 2 (ProSAP2)Shank3 proteinSH3 and multiple ankyrin repeat domains 3

Inhibition of integrin activation via sequestration of active Rap1 and R-Ras, antagonizing the Rap1–RIAM–talin pathway. Regulation of synaptic plasticity via scaffolding and organization of postsynaptic complexes Control of actin cytoskeleton dynamics