PSKH1 Kinase Activity Is Differentially Modulated via Allosteric Binding of Ca2+ Sensor Proteins

Authors

Christopher R Horne
Toby A Dite
Samuel N Young
Lucy J Mather
Laura F Dagley
Jared L Johnson
Tomer M Yaron-Barir
Emily M Huntsman
Leonard A Daly
Dominic P Byrne
Antonia L Cadell
Boaz H Ng
Jumana Yousef
Dylan H Multari
Lianju Shen
Luke M McAloon
Gerard Manning
Mark A Febbraio
Anthony R Means
Lewis C Cantley
Maria C Tanzer
David R Croucher
Claire E Eyers
Patrick A Eyers
John W Scott
James M Murphy

Language

English

Publication Date

2-25-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2420961122

PMID

39964718

PMCID

PMC11873932

PubMedCentral® Posted Date

2-18-2025

PubMedCentral® Full Text Version

Post-print

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 Ca2+ sensor proteins, promote or suppress activity. Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca2+-Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca2+ 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 Ca2+ 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 Ca2+ sensors may act more broadly to tune kinase activities by detecting and decoding extremes of intracellular Ca2+ concentrations.

Keywords

Humans, Allosteric Regulation, Calcium, Protein Serine-Threonine Kinases, Calcium-Binding Proteins, HEK293 Cells, Protein Binding, Adaptor Proteins, Signal Transducing, Calmodulin, protein kinase, calmodulin, UNC119B, reticulocalbin, allostery

Published Open-Access

yes

Recommended Citation

Horne, Christopher R; Dite, Toby A; Young, Samuel N; et al., "PSKH1 Kinase Activity Is Differentially Modulated via Allosteric Binding of Ca2+ Sensor Proteins" (2025). Children’s Nutrition Research Center Staff Publications. 262.
https://digitalcommons.library.tmc.edu/staff_pub/262