摘要
of main observation and conclusion The active Ras subfamily GTPases,R apl 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 Raplb and the Ras-mimetic Raplb 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.
基金
We thank SSRF BL17U1 and BL19U1 for X-ray beam time,Prof.Jiahuai Han for the full-length SHANK3,and Rap1b cDNA.Thiswork was supported by grants from the National Key R&D Pro-gram of China(2016YFAO501903)
the National Natural Science Foundation of China(21822705.21621002,91753113)
the Sci-ence and Technology Commission of Shanghai Municipality(15JC1400400)
and the Strategic Priority Research Program of theChinese Academy of Sciences(XDB20000000).
