Autism associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses

Abstract

Members of the SH3- and ankyrin-rich repeat (SHANK) protein family are considered as master scaffolds of the post-synaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this work, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3. In a proof-of-principle study we demonstrate that both mutant proteins show indeed distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and surprisingly also distal structural disturbances of protein folding result in altered synaptic targeting and changes of protein turnover at synaptic sites.