Mechanistic Insights into the Interactions of Ras Subfamily GTPases with the SPN Domain of Autism‐associated SHANK3†

Abstract

Summary of main observation and conclusionThe active Ras subfamily GTPases, Rap1 and Ras, can be specifically recognized by the SPN domain of SHANK3, mutations of which are associated with many neuropsychiatric diseases such as autism spectrum disorder (ASD). However, the mechanistic bases underlying the interactions of SHANK3 SPN and those Ras subfamily proteins are still elusive. Here, we reported the crystal structures of SHANK3 SPN in complex with the GTP‐bound Rap1b and the Ras‐mimetic Rap1b E30D/K31E double mutant. In addition to uncovering the detailed molecular mechanism governing the specific interactions of SHANK3 SPN with those Ras subfamily proteins, the determined structures also reveal a general binding mode between SHANK3 SPN and its associated Ras subfamily proteins. Finally, our study also provides mechanistic insights into two ASD‐causing R12C and L68P mutations found in the SPN domain of SHANK3, and expands our understanding of the etiology of neuropsychiatric diseases caused by defective SHANK3.