Loading...
PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins
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.
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.
Author
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
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.
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
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.
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
protein, kinase, calmodulin, UNC119B, reticulocalbin, allostery
Date
2025
Type
Journal article
Journal
Proceedings of the National Academy of Sciences of the United States of America
Book
Volume
122
Issue
8
Page Range
1-10
Article Number
Article e2420961122
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
Published as ‘gold’ (paid) open access
License
CC BY 4.0
File Access
Open
Notes
Copyright © 2025 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/).