Biomolecular interactions between human recombinant β-MyHC and cMyBP-Cs implicated in familial hypertrophic cardiomyopathy

Flavigny, Jeanne; Robert, Philippe; Camelin, Jean-Claude; Schwartz, Ketty; Carrier, Lucie; Berrebi-Bertrand, Isabelle

doi:10.1016/j.cardiores.2003.07.001

Cited by 22 publications

(13 citation statements)

References 36 publications

(29 reference statements)

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“…24 Consistently, simultaneous staining of myomasp/LRRC39 with the Z-disc-specific calsarcin-1 antibody 25 revealed no overlapping fluorescence pattern, excluding a sarcomeric Z-disc localization for myomasp/ LRRC39 ( Figure 4A). Likewise, A-band staining was investigated with a MYBPC3 antibody, because MYBPC3 has been shown to bind to the myosin subfragment-2 (S2) neck region with its C terminus 26 and to localize to the sarcomeric A-band. 27 Simultaneous staining of MYBPC3 and myomasp/ LRRC39 excluded an A-band localization of myomasp/ LRRC39 ( Figure 4A).…”

Section: Myomasp/lrrc39 Is a Novel Component Of The Sarcomeric M-bandmentioning

confidence: 99%

Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Will

Eden

Just

et al. 2010

Circulation Research

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Rationale and Objective:The M-band represents a transverse structure in the center of the sarcomeric A-band and provides an anchor for the myosin-containing thick filaments. In contrast to other sarcomeric structures, eg, the Z-disc, only few M-band-specific proteins have been identified to date, and its exact molecular composition remains unclear. Methods and Results:Using a bioinformatic approach to identify novel heart-and muscle-specific genes, we found a leucine rich protein, myomasp (Myosin-interacting, M-band-associated stress-responsive protein)/ LRRC39. RT-PCR and Northern and Western blot analyses confirmed a cardiac-enriched expression pattern, and immunolocalization of myomasp revealed a strong and specific signal at the sarcomeric M-band. Yeast 2-hybrid screens, as well as coimmunoprecipitation experiments, identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp. Knockdown of myomasp in neonatal rat ventricular myocytes (NRVCMs) led to a significant upregulation of the stretch-sensitive genes GDF-15 and BNP. Conversely, the expression of MYH7 and the M-band proteins myomesin-1 and -2 was found to be markedly reduced. Mechanistically, knockdown of myomasp in NRVCM led to a dose-dependent suppression of serum response factor-dependent gene expression, consistent with earlier observations linking the M-band to serum response factor-mediated signaling. Finally, downregulation of myomasp/LRRC39 in spontaneously beating engineered heart tissue constructs resulted in significantly lower force generation and reduced fractional shortening. Likewise, knockdown of the myomasp/LRRC39 ortholog in zebrafish resulted in severely impaired heart function and cardiomyopathy in vivo. Key Words: myocytes Ⅲ cardiac Ⅲ stretch Ⅲ serum response factor Ⅲ M-band T he sarcomeres of cardiac and skeletal muscle represent the basic molecular unit for contractile force generation and transmission. 1 The thin filaments of the sarcomere consist of actin fibers that are crosslinked at the Z-disc, whereas the thick filaments, mainly composed of myosin molecules, are attached to the M-band, which provides lateral stabilization. 2 Beyond a mere mechanical function, these crucial subsarcomeric structures and their molecular components have been implicated in the regulation of the dynamics of muscle contraction and the sensing of cardiomyocyte stress. 3,4 Moreover, the sarcomeric Z-disc, as well as the M-band, has increasingly been recognized as a hub for signaling pathways that mediate diverse intracellular processes including cell growth and differentiation, as well as protein turnover and gene expression. 2,4 -6 At the level of the sarcomeric Z-disc, the conversion of structural and mechanical demands to gene transcription is mediated by several specific pathways, including calcium-dependent signaling via the calcineurin- NFATc pathway, 7-9 extracellular signal-regulated kinase 2, 10 protein kinase C, 11 and the ubiquitin modification machinery (eg, via MURF-ligases). 12,13 More recently, the ...

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Section: Myomasp/lrrc39 Is a Novel Component Of The Sarcomeric M-bandmentioning

confidence: 99%

Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Will

Eden

Just

et al. 2010

Circulation Research

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“…1 online), a key constituent of the thick filaments localized to doublets in the C-zone of the A-band of the sarcomere. By binding to myosin4-6, titin7 and actin8, cMyBP-C contributes to the structural integrity of the sarcomere and regulates cardiac contractility in response to adrenergic stimulation9,10. Because individuals who have heritable cardiomyopathies with cMyBP-C defects have a disorganized sarcomeric structure and late-onset symptoms, MYBPC3 has emerged as a candidate gene for increased risk of heart failure through either hypertrophic or dilated cardiomyopathies (HCM or DCM)11,12.…”

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confidence: 99%

A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

et al. 2009

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Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown1. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3–13), P = 2 × 10−6; replication study OR = 8.59 (3.19–25.05), P = 3 × 10−8; combined OR = 6.99 (3.68–13.57), P = 4 × 10−11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (~4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.

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“…The increase in proteasomal workload associated with clearing of these mutated forms of cMyBP-C results in impairment of proteolytic capacity. 114 Frameshift mutant cMyBP-C proteins are expressed at markedly lower levels in muscle, despite the fact that the mRNA levels of these mutant forms of cMyBP-C match the wild-type cMyBP-C mRNA levels, 114 in both humans 115,116 and transgenic mice. 117,118 Experimentally, if the 26S proteasome is inhibited, expression of the truncated cMyBP-C mutant protein increases to that of wild-type cMyBP-C levels, supporting a role for proteasomal degradation in the control of cMyBP-C protein expression levels.…”

Section: The Role Of Cardiac E3 Ligasesmentioning

confidence: 99%

“…Paradoxically, although the UPS is activated to remove mutant cMyBP-C proteins from the cell, over time, the increased proteasomal workload associated with this quality control mechanism results in a breakdown in activity of the proteasome, ultimately leading to the accumulation of mutated cMyBP-C proteins. 114 As such, truncated cMyBP-Cs act as both substrates of the UPS and obstructers of the proteolytic process, a dichotomy that is shared with certain protein mutants that accumulate in Alzheimer’s disease and other storage-related neurological conditions. 119 The specific E3 ligases that target either wild-type or mutant cMyBP-C are currently unknown.…”

Section: The Role Of Cardiac E3 Ligasesmentioning

confidence: 99%

The Ubiquitin–Proteasome System and Cardiovascular Disease

Powell

Herrmann

Lerman

et al. 2012

Progress in Molecular Biology and Translational Science

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Over the past decade, the role of the ubiquitin–proteasome system (UPS) has been the subject of numerous studies to elucidate its role in cardiovascular physiology and pathophysiology. There have been many advances in this field including the use of proteomics to achieve a better understanding of how the cardiac proteasome is regulated. Moreover, improved methods for the assessment of UPS function and the development of genetic models to study the role of the UPS have led to the realization that often the function of this system deviates from the norm in many cardiovascular pathologies. Hence, dysfunction has been described in atherosclerosis, familial cardiac proteinopathies, idiopathic dilated cardiomyopathies, and myocardial ischemia. This has led to numerous studies of the ubiquitin protein (E3) ligases and their roles in cardiac physiology and pathophysiology. This has also led to the controversial proposition of treating atherosclerosis, cardiac hypertrophy, and myocardial ischemia with proteasome inhibitors. Furthering our knowledge of this system may help in the development of new UPS-based therapeutic modalities for mitigation of cardiovascular disease.

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Biomolecular interactions between human recombinant β-MyHC and cMyBP-Cs implicated in familial hypertrophic cardiomyopathy

Cited by 22 publications

References 36 publications

Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

The Ubiquitin–Proteasome System and Cardiovascular Disease

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