Structural and molecular determinants of CCS-mediated copper activation of MEK1/2

Author:

Grasso Michael,Bond Gavin J.ORCID,Kim Ye-JinORCID,Alwan Katherine B.ORCID,Boyd StefanieORCID,Dzebo Maria MatsonORCID,Valenzuela Sebastian,Tsang TiffanyORCID,Schibrowsky Natalie A.ORCID,Matthews Megan L.ORCID,Burslem George M.ORCID,Wittung-Stafshede PernillaORCID,Winkler Duane D.ORCID,Blackburn Ninian J.ORCID,Marmorstein RonenORCID,Brady Donita C.ORCID

Abstract

SummaryNormal physiology relies on the precise coordination of intracellular signal transduction pathways that respond to nutrient availability to balance cell growth and cell death. We recently established a critical mechanistic function for the redox-active micronutrient copper (Cu) in the canonical mitogen activated protein kinase (MAPK) pathway at the level of MEK1 and MEK2. Here we report the X-ray crystal structure of Cu-MEK1 and reveal active site chemical ligands and oxidation state specificity for MEK1 Cu coordination. Mechanistically, the Cu chaperone CCS selectively bound to and facilitated Cu transfer to MEK1. Mutations in MEK1 that disrupt Cu(I) affinity or a CCS small molecule inhibitor reduced Cu-stimulated MEK1 kinase activity. These atomic and molecular level data provide the first mechanistic insights of Cu kinase signaling and could be exploited for the development of novel MEK1/2 inhibitors that either target the Cu structural interface or blunt dedicated Cu delivery mechanisms via CCS.

Publisher

Cold Spring Harbor Laboratory

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Copper as a Novel Regulator of PERK;2022-09-02

2. Getting out what you put in: Copper in mitochondria and its impacts on human disease;Biochimica et Biophysica Acta (BBA) - Molecular Cell Research;2021-01

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