PSKH1 kinase activity is differentially modulated via allosteric binding of Ca <sup>2+</sup> sensor proteins
Abstract
Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed in prostate, lung, and kidney cancers. However, little is known about PSKH1 regulatory mechanisms, leading to its classification as a “dark” kinase. Here, we used biochemistry and mass spectrometry to define PSKH1’s consensus substrate motif, protein interactors, and how interactors, including Ca 2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca 2+ -Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca 2+ sensor of the Cab45, Reticulocalbin, Erc55, Calumenin (CREC) family, Reticulocalbin-3, suppressed PSKH1 catalytic activity. In addition to antagonistic regulation of the PSKH1 kinase domain by Ca 2+ sensing proteins, we identified UNC119B as a protein interactor that activates PSKH1 via direct engagement of the kinase domain. Our findings identify complementary allosteric mechanisms by which regulatory proteins tune PSKH1’s catalytic activity and raise the possibility that different Ca 2+ sensors may act more broadly to tune kinase activities by detecting and decoding extremes of intracellular Ca 2+ concentrations.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (26)
Christopher R. Horne
Walter and Eliza Hall Institute of Medical Research
Toby A. Dite
Walter and Eliza Hall Institute of Medical Research
Samuel N. Young
Walter and Eliza Hall Institute of Medical Research
Lucy J. Mather
Walter and Eliza Hall Institute of Medical Research
Laura F. Dagley
Walter and Eliza Hall Institute of Medical Research
Jared L. Johnson
Meyer Cancer Center, Weill Cornell Medicine
Tomer M. Yaron-Barir
Meyer Cancer Center, Weill Cornell Medicine
Emily M. Huntsman
Meyer Cancer Center, Weill Cornell Medicine
Leonard A. Daly
Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool
Dominic P. Byrne
Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool
Antonia L. Cadell
Cancer Ecosystems Program, Garvan Institute of Medical Research
Boaz H. Ng
Cancer Ecosystems Program, Garvan Institute of Medical Research
Jumana Yousef
Walter and Eliza Hall Institute of Medical Research
Dylan H. Multari
Walter and Eliza Hall Institute of Medical Research
Lianju Shen
Walter and Eliza Hall Institute of Medical Research
Luke M. McAloon
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Gerard Manning
NuaBio Research
Mark A. Febbraio
Anthony R. Means
Molecular and Cellular Biology, Baylor College of Medicine
Lewis C. Cantley
Maria C. Tanzer
David R. Croucher
Cancer Ecosystems Program, Garvan Institute of Medical Research
Claire E. Eyers
Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool
Patrick A. Eyers
Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool
John W. Scott
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
James M. Murphy