Activating mutations drive human MEK1 kinase using a gear-shifting mechanism

There is an unmet need to classify cancer-promoting kinase mutations in a mechanistically cognizant way. The challenge is to understand how mutations stabilize different kinase configurations to alter function, and how this influences pathogenic potential of the kinase and its responses to therapeut...

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Veröffentlicht in:Biochemical journal 2023-11, Vol.480 (21), p.1733-1751
Hauptverfasser: Patil, Keshav, Wang, Yiming, Chen, Zhangtao, Suresh, Krishna, Radhakrishnan, Ravi
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container_end_page 1751
container_issue 21
container_start_page 1733
container_title Biochemical journal
container_volume 480
creator Patil, Keshav
Wang, Yiming
Chen, Zhangtao
Suresh, Krishna
Radhakrishnan, Ravi
description There is an unmet need to classify cancer-promoting kinase mutations in a mechanistically cognizant way. The challenge is to understand how mutations stabilize different kinase configurations to alter function, and how this influences pathogenic potential of the kinase and its responses to therapeutic inhibitors. This goal is made more challenging by the complexity of the mutational landscape of diseases, and is further compounded by the conformational plasticity of each variant where multiple conformations coexist. We focus here on the human MEK1 kinase, a vital component of the RAS/MAPK pathway in which mutations cause cancers and developmental disorders called RASopathies. We sought to explore how these mutations alter the human MEK1 kinase at atomic resolution by utilizing enhanced sampling simulations and free energy calculations. We computationally mapped the different conformational stabilities of individual mutated systems by delineating the free energy landscapes, and showed how this relates directly to experimentally quantified developmental transformation potentials of the mutations. We conclude that mutations leverage variations in the hydrogen bonding network associated with the conformational plasticity to progressively stabilize the active-like conformational state of the kinase while destabilizing the inactive-like state. The mutations alter residue-level internal molecular correlations by differentially prioritizing different conformational states, delineating the various modes of MEK1 activation reminiscent of a gear-shifting mechanism. We define the molecular basis of conversion of this kinase from its inactive to its active state, connecting structure, dynamics, and function by delineating the energy landscape and conformational plasticity, thus augmenting our understanding of MEK1 regulation.
doi_str_mv 10.1042/BCJ20230281
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subjects Gain of Function Mutation
Humans
Mutation
Neoplasms - metabolism
title Activating mutations drive human MEK1 kinase using a gear-shifting mechanism
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