蛋白激酶结构域
激酶
点突变
蛋白激酶A
生物
活动站点
突变
蛋白质结构
化学
细胞生物学
生物化学
遗传学
酶
基因
突变体
作者
Saeideh Nakhaei-Rad,Fatemeh Janatifard,Radovan Dvorsky,Mohammad Reza Ahmadian,Mohammad R. Housaindokht
标识
DOI:10.1080/07391102.2023.2187221
摘要
The germline mutations in the C-terminus of CRAF kinase, particularly L603, and S612T/L613V, are associated with congenital heart disorders, for example, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The experimental data suggest that genetic alternation at position 603 impairs, while those at positions 612/613 enhance the CRAF kinase activity. However, the underlying mechanistic details by which these mutations increase or decrease kinase activity remain elusive. Therefore, we applied molecular dynamic simulation to investigate the impacts of these point mutations on the conformation of the CRAF kinase domain. The results revealed that the substitution of Leucine 603 for proline transits the kinase domain to a state that exhibits the molecular hallmarks of an inactive kinase, for example, a closed activation loop, 'αC-helix out' conformation and a distorted regulatory hydrophobic spine. However, two HCM-associated variants (S612T and L613V) show features of an active conformation, such as an open activation loop conformation, 'αC-helix in', the assembly of the hydrophobic spine, and more surface-exposed catalytic residues of phosphoryl transfer reaction. Overall, our study provides a mechanistic basis for the contradictory effects of the CRAF variants associated with HCM and DCM.
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