School of Life Sciences, Southern University of Science and Technology , Shenzhen, China.
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, China.
J Cell Biol. 2023 Dec 4;222(12). doi: 10.1083/jcb.202307117. Epub 2023 Oct 3.
IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.
IQSEC2（又名 BRAG1）是一种在突触中高度富集的鸟嘌呤核苷酸交换因子（GEF）。作为一种主要的神经发育障碍风险基因，在伴有其他发育、神经和精神症状的智力障碍患者中，已鉴定出许多 IQSEC2 突变，尽管其潜在的分子机制尚不清楚。本研究中呈现的 IQSECs 的原子结构以及生化分析揭示了所有 IQSECs 的自动抑制和 Ca2+依赖性变构激活机制，并合理说明了每个鉴定出的 Iqsec2 突变如何改变酶的结构和功能。模拟 IQSEC2 两种致病变体（R359C 和 Q801P）的转基因小鼠在患者中再现了不同的临床表型，其中一个变体激活，另一个变体抑制酶的 GEF 活性。我们的研究表明，一个基因（如 IQSEC2）上的不同突变可能具有不同的神经表型，因此需要不同的治疗策略。
