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Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

McNamara, James W; Parker, Benjamin L; Voges, Holly K; Mehdiabadi, Neda R; Bolk, Francesca; Ahmad, Feroz; Chung, Jin D; ... Elliott, David A; + view all (2023) Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle. Nature Cardiovascular Research , 2 pp. 159-173. 10.1038/s44161-023-00219-9. Green open access

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Abstract

Muscle contraction is driven by the molecular machinery of the sarcomere. As phosphorylation is a critical regulator of muscle function, the identification of regulatory kinases is important for understanding sarcomere biology. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 is an essential component of the M-band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant. ALPK3-dependent phosphopeptides were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein sequestosome-1 (SQSTM1) (also known as p62). Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis.

Type: Article
Title: Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s44161-023-00219-9
Publisher version: https://doi.org/10.1038/s44161-023-00219-9
Language: English
Additional information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Cardiovascular biology, Cell biology, Cell signalling, Phosphorylation, Stem-cell differentiation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10171983
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