Title : ( Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain )
Authors: Saeideh Nakhaeirad , Fatemeh Janati fard , Radovan Dvorskyd , Mohammad R. Ahmadian , Mohammad Reza Housaindokht ,Access to full-text not allowed by authors
Abstract
The germline mutations in the C-terminus of CRAF kinase, particularly L603, and S612T/ L613V, are associated with congenital heart disorders, e.g., dilated cardiomyopathies (DCM) and hypertrophic cardiomyopathy (HCM). The experimental data indicate that genetic alternation at position 603 residue impairs whereas at 612/613 residues enhance the CRAF kinase activity. However, the underlying mechanistic details by which these mutations increase or decrease kinase activity remain elusive. Therefore, we apply molecular dynamic simulation to investigate the impact of these point mutations on the conformation of the CRAF kinase domain. The results reveal that the substitution of Leucine 603 for proline transits the kinase domain into a state with molecular hallmarks of the inactive kinase, e.g., a closed activation loop, “α-C helix out” conformation and a distorted regulatory hydrophobic spine. Two HCM-associated variants (S612T and L613V) show features of 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 transferring reaction. Overall, our study provides a mechanistic basis for the contradictory effects of the HCM and DCM-associated CRAF variants.
Keywords
, CRAF, kinase domain, MAPK pathway, molecular dynamic simulation, conformational changes, catalytic activity, mutation, serine/threonine kinase, cardiomyopathy, RAF1, RASopathy, Noonan syndrome@article{paperid:1093540,
author = {Nakhaeirad, Saeideh and Janati Fard, Fatemeh and Radovan Dvorskyd and Mohammad R. Ahmadian and Housaindokht, Mohammad Reza},
title = {Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain},
journal = {Journal of Biomolecular Structure and Dynamics},
year = {2023},
volume = {41},
number = {24},
month = {December},
issn = {0739-1102},
pages = {15328--15338},
numpages = {10},
keywords = {CRAF; kinase domain; MAPK pathway; molecular dynamic simulation; conformational changes; catalytic activity; mutation; serine/threonine kinase; cardiomyopathy; RAF1; RASopathy; Noonan syndrome},
}
%0 Journal Article
%T Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain
%A Nakhaeirad, Saeideh
%A Janati Fard, Fatemeh
%A Radovan Dvorskyd
%A Mohammad R. Ahmadian
%A Housaindokht, Mohammad Reza
%J Journal of Biomolecular Structure and Dynamics
%@ 0739-1102
%D 2023