Abstract
Obscurin is a giant cytoskeletal protein with structural and regulatory roles encoded by the OBSCN gene. Recently, mutations in OBSCN were associated with the development of different forms of cardiomyopathies, including hypertrophic cardiomyopathy (HCM). We previously reported that homozygous mice carrying the HCM-linked R4344Q obscurin mutation develop arrhythmia by 1-year of age under sedentary conditions characterized by increased heart rate, frequent incidents of premature ventricular contractions, and episodes of spontaneous ventricular tachycardia. In an effort to delineate the molecular mechanisms that contribute to the observed arrhythmic phenotype, we subjected protein lysates prepared from left ventricles of 1-year old R4344Q and wild-type mice to comparative proteomics analysis using tandem mass spectrometry; raw data are available via ProteomeXchange with identifier PXD017314. We found that the expression levels of proteins involved in cardiac function and disease, cytoskeletal organization, electropotential regulation, molecular transport and metabolism were significantly altered. Moreover, phospho-proteomic evaluation revealed changes in the phosphorylation profile of Ca2+ cycling proteins, including sAnk1.5, a major binding partner of obscurin localized in the sarcoplasmic reticulum; notably, this is the first report indicating that sAnk1 undergoes phosphorylation. Taken together, our findings implicate obscurin in diverse cellular processes within the myocardium, which is consistent with its multiple binding partners, localization in different subcellular compartments, and disease association.
Highlights
Muscle contraction is a highly regulated process that depends on the coordinated assembly of the sarcomeric cytoskeleton and internal membrane systems regulating Ca2+ cycling
The R4344Q obscurin mutation was originally identified via genetic screening in a young adult Japanese patient presenting with hypertrophic cardiomyopathy (HCM) (Arimura et al, 2007)
The patient’s mother was diagnosed with HCM, and she was not screened for the mutation, it was postulated that the index patient most likely inherited the mutation from her since the father did not carry it and did not develop HCM (Arimura et al, 2007)
Summary
Muscle contraction is a highly regulated process that depends on the coordinated assembly of the sarcomeric cytoskeleton and internal membrane systems regulating Ca2+ cycling. Given its unique position at the periphery of Z-disks and M-bands, obscurin mediates binding to structural, regulatory and membrane-associated proteins residing in different subcellular compartments via its adhesion and signaling motifs (Bagnato et al, 2003; KontrogianniKonstantopoulos et al, 2003; Bowman et al, 2007; Fukuzawa et al, 2008; Ackermann et al, 2009; Ford-Speelman et al, 2009; Hu and Kontrogianni-Konstantopoulos, 2013; Randazzo et al, 2013; Qadota et al, 2016; Shriver et al, 2016). Our studies reveal alterations in the expression levels and post-translational regulation via phosphorylation of proteins involved in major pathophysiological processes and highlight the involvement of obscurin in their modulation
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