PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins PMID: 39964718

Target-related Cytokines

2026-09-23

PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins

Proc Natl Acad Sci U S A. 2025 Feb 25;122(8):e2420961122. doi: 10.1073/pnas.2420961122.

Christopher R Horne ¹ ² ³ , Toby A Dite ¹ ² , Samuel N Young ¹ , Lucy J Mather ¹ , Laura F Dagley ¹ ² , Jared L Johnson ⁴ ⁵ ⁶ , Tomer M Yaron-Barir ⁴ ⁷ ⁸ , Emily M Huntsman ⁴ ⁷ , Leonard A Daly ⁹ ¹⁰ , Dominic P Byrne ⁹ , Antonia L Cadell ¹¹ , Boaz H Ng ¹¹ , Jumana Yousef ¹ ² , Dylan H Multari ¹ ² , Lianju Shen ¹ , Luke M McAloon ³ ¹² ¹³ , Gerard Manning ¹⁴ , Mark A Febbraio ³ , Anthony R Means ¹⁵ , Lewis C Cantley ⁴ ⁵ ⁶ , Maria C Tanzer ¹ ² , David R Croucher ¹¹ ¹⁶ , Claire E Eyers ⁹ ¹⁰ , Patrick A Eyers ⁹ , John W Scott ^# ³ ¹³ ¹⁷ , James M Murphy ^# ¹ ² ³

Affiliations

1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
2. Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
3. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
4. Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
5. Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
6. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
7. Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021.
8. Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032.
9. Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
10. Centre for Proteome Research, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
11. Cancer Ecosystems Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
12. School of Behavioural and Health Sciences, Australian Catholic University, Fitzroy, VIC 3065, Australia.
13. St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
14. NuaBio Research, Burlingame, CA 94010.
15. Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
16. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, NSW 2010, Australia.
17. The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia.
# Contributed equally.

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

UNC119B; allostery; calmodulin; protein kinase; reticulocalbin.