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

• 成果类型: Article
• 署名作者: Horne, Christopher R.; Dite, Toby A.; Young, Samuel N.; Mather, Lucy J.; Dagley, Laura F.; Johnson, Jared L.; Yaron-Barir, Tomer M.; Huntsman, Emily M.; Daly, Leonard A.; Byrne, Dominic P.; Cadell, Antonia L.; Ng, Boaz H.; Yousef, Jumana; Multari, Dylan H.; Shen, Lianju; Mcaloon, Luke M.; Manning, Gerard; Febbraio, Mark A.; Means, Anthony R.; Cantley, Lewis C.; Tanzer, Maria C.; Croucher, David R.; Eyers, Claire E.; Eyers, Patrick A.; Scott, John W.; Murphy, James M.
• 署名单位: Walter & Eliza Hall Institute; University of Melbourne; Monash University; Cornell University; Weill Cornell Medicine; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard Medical School; Cornell University; Weill Cornell Medicine; Columbia University; University of Liverpool; University of Liverpool; Garvan Institute of Medical Research; Australian Catholic University; St. Vincent's Institute of Medical Research; Baylor College of Medicine; University of New South Wales Sydney; Florey Institute of Neuroscience & Mental Health
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15061
• DOI: 10.1073/pnas.2420961122
• 发表日期: 2025-02-25
• 关键词: multiple ef-hand; endoplasmic-reticulum; serine kinase; calcium; identification; cargo; calmodulin; release; unc119; FAMILY

摘要

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 canoninistic 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.