Mechanistic studies of the interaction between Shank3 and CaMKIIα

Shank and CaMKII are two extremely abundant proteins in the postsynaptic densities of excitatory synapses. Both classes of proteins are vitally important for synapse development and activities. Mutations of Shank are known to cause syndromic and idiopathic ASD, as well as other psychiatric and neurodevelopmental disorders. Mutations of CaMKII are known to impair learning and memory in animal models. However, the molecular mechanisms underlying psychiatric disorders resulting from the mutations of these two families of synaptic proteins are still poorly understood.

Mingjie Zhang’s laboratory focuses on neuronal structural biology, and his lab previously discovered an interaction between Shank3 and CaMKIIα during a search for binding partners of the Shank3 N-terminal Ankyrin repeats-containing domain. Zhang now proposes to investigate the molecular mechanism governing the specificity of this interaction by obtaining an atomic resolution picture of the structure of the Shank3 N-terminal Ankyrin repeats in complex with CaMKIIα. The team will also study how the interaction between Shank3 and CaMKIIα is regulated by neuronal activity. Finally, Zhang’s group plans to investigate how Shank3 mutations found in individuals with autism might alter the formation and function of the Shank3/CaMKIIα complex at synapses. The findings from these studies will help advance our understanding of the interactions between these two vitally important synaptic proteins and how autism-linked mutations might disrupt the function of this complex.