The copper chaperone CCS facilitates copper binding to MEK1/2 to promote kinase activation
Journal article, 2021

Normal physiology relies on the precise coordination of intracellular signaling pathways that respond to nutrient availability to balance cell growth and cell death. The canonical mitogen-activated protein kinase pathway consists of the RAFMEK- ERK signaling cascade and represents one of the most well-defined axes within eukaryotic cells to promote cell proliferation, which underscores its frequent mutational activation in human cancers. Our recent studies illuminated a function for the redox-active micronutrient copper (Cu) as an intracellular mediator of signaling by connecting Cu to the amplitude of mitogen-activated protein kinase signaling via a direct interaction between Cu and the kinases MEK1 and MEK2. Given the large quantities of molecules such as glutathione and metallothionein that limit cellular toxicity from free Cu ions, evolutionarily conserved Cu chaperones facilitate efficient delivery of Cu to cuproenzymes. Thus, a dedicated cellular delivery mechanism of Cu to MEK1/2 likely exists. Using surface plasmon resonance and proximity-dependent biotin ligase studies, we report here that the Cu chaperone for superoxide dismutase (CCS) selectively bound to and facilitated Cu transfer to MEK1. Mutants of CCS that disrupt Cu(I) acquisition and exchange or a CCS small-molecule inhibitor were used and resulted in reduced Cu-stimulated MEK1 kinase activity. Our findings indicate that the Cu chaperone CCS provides fidelity within a complex biological system to achieve appropriate installation of Cu within the MEK1 kinase active site that in turn modulates kinase activity and supports the development of novel MEK1/2 inhibitors that target the Cu structural interface or blunt dedicated Cu delivery mechanisms via CCS.

Author

Michael Grasso

University of Pennsylvania

Gavin J. Bond

University of Pennsylvania

Ye Jin Kim

University of Pennsylvania

Stefanie Boyd

University of Texas at Dallas

Maria Matson Dzebo

Chalmers, Biology and Biological Engineering, Chemical Biology

Sebastian Valenzuela

Chalmers, Biology and Biological Engineering, Chemical Biology

Tiffany Tsang

University of Pennsylvania

Natalie A. Schibrowsky

University of Pennsylvania

Katherine B. Alwan

Oregon Health and Science University

Ninian J. Blackburn

Oregon Health and Science University

George M. Burslem

University of Pennsylvania

Pernilla Wittung Stafshede

Chalmers, Biology and Biological Engineering, Chemical Biology

Duane D. Winkler

University of Texas at Dallas

Ronen Marmorstein

University of Pennsylvania

Donita C. Brady

University of Pennsylvania

Journal of Biological Chemistry

0021-9258 (ISSN) 1083-351X (eISSN)

Vol. 297 6 101314

Mekanismer för kopparjontransport i mänskliga celler

Swedish Research Council (VR) (2015-03881), 2016-01-01 -- 2020-12-31.

Subject Categories

Biochemistry and Molecular Biology

Cell and Molecular Biology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

DOI

10.1016/j.jbc.2021.101314

PubMed

34715128

More information

Latest update

12/20/2021