Journal article
Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle
JW McNamara, BL Parker, HK Voges, NR Mehdiabadi, F Bolk, F Ahmad, JD Chung, N Charitakis, J Molendijk, ATL Zech, S Lal, M Ramialison, K Karavendzas, HL Pointer, P Syrris, LR Lopes, PM Elliott, GS Lynch, RJ Mills, JE Hudson Show all
Nature Cardiovascular Research | Published : 2023
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 sa..
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Awarded by Australian Government
Funding Acknowledgements
We thank the National Health and Medical Research Council of Australia (E.R.P., D.A.E., B.L.P.; grant nos. GNT2008376, 1160256 and 1160257), the Australian Research Council (E.R.P.; grant no. DP190101972), the Heart Foundation of Australia (E.R.P., D.A.E.; grant nos. 104997 and 105146), the Medical Research Future Fund (E.R.P., D.A.E.; grant nos. MRF2007316 and MRF2007471), the Stafford Fox Medical Research Foundation (E.R.P.), the Australian Genomics Health Alliance (J.W.M., E.R.P., D.A.E.), the Royal Children's Hospital Foundation (E.R.P.) and the Murdoch Children's Research Institute (MCRI) Early Career Researcher Award (J.W.M.) for grant and fellowship support. The MCRI is supported by the Victorian Government's Operational Infrastructure Support Program. E.R.P. and D.A.E. are principal investigators of the Novo Nordisk Foundation Center for Stem Cell Medicine, which is supported by Novo Nordisk Foundation grant no. NNF21CC0073729. L.R.L. is supported by a UK Research and Innovation Medical Research Council clinical academic research partnership award (no. MR/T005181/1). The generation of the Alpk3W1538X mice used in this study was supported by Phenomics Australia and the Australian Government through the National Collaborative Research Infrastructure Strategy program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.