Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA889737 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21874460_1.fastq.gz | Fastqsanger.gz | |||
| SRR21874460_2.fastq.gz | Fastqsanger.gz | |||
| SRR21874461_1.fastq.gz | Fastqsanger.gz | |||
| SRR21874461_2.fastq.gz | Fastqsanger.gz | |||
| SRR21874462_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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