Molecular annotation of G protein variants in a neurological disorder.
Molecular annotation of G protein variants in a neurological disorder.
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神经系统疾病中 G 蛋白变异的分子注释。
DOI：
10.1016/j.celrep.2023.113462
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发表时间：
2023
期刊：
影响因子：
8.8
通讯作者：
Dohlman,HenrikG
中科院分区：
文献类型：
--
作者：
Knight,KevinM;Obarow,ElizabethG;Wei,Wenyuan;Mani,Sepehr;Esteller,MariaI;Cui,Meng;Ma,Ning;Martin,SarahA;Brinson,Emily;Hewitt,Natalie;Soden,GabyM;Logothetis,DiomedesE;Vaidehi,Nagarajan;Dohlman,HenrikG
异源三聚体G蛋白介导细胞外化学信息以产生适当的细胞内反应。GNAO 1编码G蛋白α o亚基，其点突变与以癫痫发作、运动障碍、智力残疾和发育迟缓（GNAO 1障碍）为特征的致病性疾病有关。然而，这些突变对G蛋白结构和功能的影响尚不清楚。在这里，我们报告了55个突变对Gα构象、热稳定性、核苷酸结合和水解的影响，以及与Gβγ亚基、受体和效应子的相互作用。我们的工作揭示了四组功能不同的突变体，包括一组隔离受体和另一组隔离Gβγ，两者都以遗传显性方式起作用。这些发现提供了对疾病相关突变的更全面的理解，并揭示了GNAO 1疾病可能由多种机制上不同的疾病组成，这些疾病可能需要多种治疗策略。
Heterotrimeric G proteins transduce extracellular chemical messages to generate appropriate intracellular responses. Point mutations inGNAO1, encoding the G protein αosubunit, have been implicated in a pathogenic condition characterized by seizures, movement disorders, intellectual disability, and developmental delay (GNAO1 disorder). However, the effects of these mutations on G protein structure and function are unclear. Here, we report the effects of 55 mutations on Gαoconformation, thermostability, nucleotide binding, and hydrolysis, as well as interaction with Gβγ subunits, receptors, and effectors. Our effort reveals four functionally distinct groups of mutants, including one group that sequesters receptors and another that sequesters Gβγ, both acting in a genetically dominant manner. These findings provide a more comprehensive understanding of disease-relevant mutations and reveal that GNAO1 disorder is likely composed of multiple mechanistically distinct disorders that will likely require multiple therapeutic strategies.