Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants.
Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants.
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DOI：
10.1016/j.jbc.2022.102361
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发表时间：
2022-09
影响因子：
4.8
通讯作者：
Koleske, Anthony J.
中科院分区：
文献类型：
--
作者：
Bircher, Josie E.;Corcoran, Ellen E.;Lam, TuKiet T.;Trnka, Michael J.;Koleske, Anthony J.
TRIO编码一种细胞骨架调节蛋白，具有三个催化结构域-两个鸟嘌呤交换因子（GEF）结构域，GEF 1和GEF 2，和一个激酶结构域-以及几个尚未被广泛研究的辅助结构域。已知TRIO基因中的功能损伤变体在患有神经发育障碍（NDD）的个体中富集。GEF 1结构域或9个相邻血影蛋白重复序列（SR）中的疾病变体在NDD中富集，表明GEF 1活性失调与这些疾病有关。我们在这里提供的证据表明，三个SR与GEF 1结构域的分子内相互作用，以抑制其酶活性。我们证明，SRs 6-9降低GEF 1的催化活性在体外和细胞中，并显示在SR 8和GEF 1结构域的NDD相关的变体缓解这种自抑制约束。我们的结果从化学交联和生物层干涉表明，SR主要接触的pleckstrin同源区域的GEF 1结构域，减少GEF 1结合到小的GTstrin Rac 1。总之，我们的研究结果揭示了一个关键的调控机制，通常在多种NDD中被破坏，并可能为TRIO相关NDD的治疗干预提供新的靶点。
TRIO encodes a cytoskeletal regulatory protein with three catalytic domains—two guanine exchange factor (GEF) domains, GEF1 and GEF2, and a kinase domain—as well as several accessory domains that have not been extensively studied. Function-damaging variants in the TRIO gene are known to be enriched in individuals with neurodevelopmental disorders (NDDs). Disease variants in the GEF1 domain or the nine adjacent spectrin repeats (SRs) are enriched in NDDs, suggesting that dysregulated GEF1 activity is linked to these disorders. We provide evidence here that the Trio SRs interact intramolecularly with the GEF1 domain to inhibit its enzymatic activity. We demonstrate that SRs 6-9 decrease GEF1 catalytic activity both in vitro and in cells and show that NDD-associated variants in the SR8 and GEF1 domains relieve this autoinhibitory constraint. Our results from chemical cross-linking and bio-layer interferometry indicate that the SRs primarily contact the pleckstrin homology region of the GEF1 domain, reducing GEF1 binding to the small GTPase Rac1. Together, our findings reveal a key regulatory mechanism that is commonly disrupted in multiple NDDs and may offer a new target for therapeutic intervention for TRIO-associated NDDs.
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影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
通讯作者：
Carpenter AE
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
14.9
作者：
Perez-Riverol Y;Bai J;Bandla C;García-Seisdedos D;Hewapathirana S;Kamatchinathan S;Kundu DJ;Prakash A;Frericks-Zipper A;Eisenacher M;Walzer M;Wang S;Brazma A;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
9.2
作者：
Estrach, S;Schmidt, S;Debant, A
通讯作者：
Debant, A
影响因子：
4.8
作者：
Debreceni, B;Gao, Y;Zheng, Y
通讯作者：
Zheng, Y