Mechanistic Insights into the Interactions of Ras Subfamily GTPases with the SPN Domain of Autism-as

• 作 者: Xiaolong Xu Jianping Liu Yingli Wang Yaru Wang Xinyu Gong Lifeng Pan
• 机 构: State Key Laboratory of Bioorganic and Natural Products Chemistry,Center for Excellence in Molecular
• 出 处: 中国化学（英文版）
• 发表日期: 2020年12期

The 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-bbound 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.