Mechanistic Insights into the Interactions of Ras Subfamily GTPases with the SPN Domain of Autism‐associated SHANK3 †
Mechanistic Insights into the Interactions of Ras Subfamily GTPases with the SPN Domain of Autism‐associated SHANK3 †
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DOI：
10.1002/cjoc.202000278
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发表时间：
2020-07
影响因子：
5.4
通讯作者：
Xiaolong Xu;Jianping Liu;Yingli Wang;Yaru Wang;Xinyu Gong;L. Pan
中科院分区：
文献类型：
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作者：
Xiaolong Xu;Jianping Liu;Yingli Wang;Yaru Wang;Xinyu Gong;L. Pan
主要观察结果和结论Ras亚家族GTP酶Rap 1和Ras可被SHANK 3的SPN结构域特异性识别，其突变与自闭症谱系障碍（ASD）等多种神经精神疾病相关。然而，SHANK 3 SPN和Ras亚家族蛋白相互作用的机制基础仍然是难以捉摸的。在这里，我们报道了SHANK 3 SPN与GTP结合的Rap 1b和Ras模拟Rap 1b E30 D/K31 E双突变体复合的晶体结构。除了揭示SHANK 3 SPN与这些Ras亚家族蛋白特异性相互作用的详细分子机制外，所确定的结构还揭示了SHANK 3 SPN与其相关Ras亚家族蛋白之间的一般结合模式。最后，我们的研究还为SHANK 3的SPN结构域中发现的两种导致ASD的R12 C和L 68 P突变提供了机制见解，并扩展了我们对SHANK 3缺陷引起的神经精神疾病病因的理解。
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.