Abstract：
AIDA-1, encoded by ANKS1B, is an abundant postsynaptic scaffold protein essential for brain development. Mutations of ANKS1B are closely associated with various psychiatric disorders. However, very little is known regarding the molecular mechanisms underlying AIDA-1\'s involvements under physiological and pathophysiological conditions. Here, we discovered an interaction between AIDA-1 and the SynGAP family Ras-GTPase activating protein (GAP) via affinity purification using AIDA-1d as the bait. Biochemical studies showed that the PTB domain of AIDA-1 binds to an extended NPx[F/Y]-motif of the SynGAP family proteins with high affinities. The high-resolution crystal structure of AIDA-1 PTB domain in complex with the SynGAP NPxF-motif revealed the molecular mechanism governing the specific interaction between AIDA-1 and SynGAP. Our study not only explains why patients with ANKS1B or SYNGAP1 mutations share overlapping clinical phenotypes, but also allows identification of new AIDA-1 binding targets such as Ras and Rab interactors.
摘要：
AIDA-1，由ANKS1B编码，是大脑发育所必需的丰富的突触后支架蛋白。ANKS1B的突变与各种精神疾病密切相关。然而,关于AIDA-1在生理和病理生理条件下参与的分子机制知之甚少。这里,我们通过使用AIDA-1d作为诱饵的亲和纯化，发现了AIDA-1与SynGAP家族Ras-GTP酶激活蛋白（GAP）之间的相互作用。生化研究表明，AIDA-1的PTB结构域与SynGAP家族蛋白的扩展NPx[F/Y]基序结合具有高亲和力。与SynGAPNPxF基序复合的AIDA-1PTB结构域的高分辨率晶体结构揭示了控制AIDA-1与SynGAP之间特定相互作用的分子机制。我们的研究不仅解释了为什么ANKS1B或SYNGAP1突变的患者共享重叠的临床表型，但也允许鉴定新的AIDA-1结合靶标，如Ras和Rab相互作用子。
