7VMB

Crystal structure of IQSEC1-IQ motif, Sec7PH tandem in complex with calmodulin

7VMB の概要

• エントリーDOI: 10.2210/pdb7vmb/pdb
• 分子名称: IQ motif and SEC7 domain-containing protein 1, Calmodulin-1, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: complex, gef activity, metal binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 69400.00

構造登録者

Yang, W.,Zhang, M. (登録日: 2021-10-08, 公開日: 2022-10-12, 最終更新日: 2023-11-29)

主引用文献

Bai, G.,Li, H.,Qin, P.,Guo, Y.,Yang, W.,Lian, Y.,Ye, F.,Chen, J.,Wu, M.,Huang, R.,Li, J.,Lu, Y.,Zhang, M.
Ca2+-induced release of IQSEC2/BRAG1 autoinhibition under physiological and pathological conditions.
J.Cell Biol., 222:-, 2023

PubMed Abstract: 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.

PubMed: 37787765
DOI: 10.1083/jcb.202307117

実験手法

X-RAY DIFFRACTION (1.99777371992 Å)