Biomedical Research Institute, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
J Mol Biol. 2024 Jun 15;436(12):168608. doi: 10.1016/j.jmb.2024.168608. Epub 2024 May 15.
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.
AIDA-1 由 ANKS1B 编码，是一种丰富的突触后支架蛋白，对大脑发育至关重要。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的作用的分子机制知之甚少。在这里，我们通过使用 AIDA-1d 作为诱饵进行亲和纯化，发现了 AIDA-1 与 SynGAP 家族 Ras-GTPase 激活蛋白 (GAP) 之间的相互作用。生化研究表明，AIDA-1 的 PTB 结构域以高亲和力结合到 SynGAP 家族蛋白的扩展 NPx[F/Y]-基序上。AIDA-1 PTB 结构域与 SynGAP NPxF 基序的高分辨率晶体结构揭示了控制 AIDA-1 和 SynGAP 之间特异性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 突变的患者具有重叠的临床表型，而且还鉴定了新的 AIDA-1 结合靶标，如 Ras 和 Rab 相互作用蛋白。
