Cardiac myosin-binding protein C: A protein once at loose ends finds its regulatory groove

Moss, Richard L.

doi:10.1073/pnas.1602568113

Cited by 10 publications

(10 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structural studies demonstrate that each isoform affects tropomyosin position on F-actin, which, in turn, may regulate function in a graded manner. Lastly, dynamic functional experiments, which measured in vitro and in silico unloaded myocyte shortening, confirmed our principal expectation 22 : that the greater capacity to activate the thin filament results in slower relaxation kinetics. Our results suggest that cMyBP-C has distinct regulatory functions over a full range of Ca 2+ , possibly because of the dynamic range of intracellular Ca 2+ experienced on a beat-to-beat basis in the heart.…”

Section: Introductionsupporting

confidence: 72%

See 1 more Smart Citation

Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner

Lin

Mun

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Muscle contraction, which is initiated by Ca2+, results in precise sliding of myosin-based thick and actin-based thin filament contractile proteins. The interactions between myosin and actin are finely tuned by three isoforms of myosin binding protein-C (MyBP-C): slow-skeletal, fast-skeletal, and cardiac (ssMyBP-C, fsMyBP-C and cMyBP-C, respectively), each with distinct N-terminal regulatory regions. The skeletal MyBP-C isoforms are conditionally coexpressed in cardiac muscle, but little is known about their function. Therefore, to characterize the functional differences and regulatory mechanisms among these three isoforms, we expressed recombinant N-terminal fragments and examined their effect on contractile properties in biophysical assays. Addition of the fragments to in vitro motility assays demonstrated that ssMyBP-C and cMyBP-C activate thin filament sliding at low Ca2+. Corresponding 3D electron microscopy reconstructions of native thin filaments suggest that graded shifts of tropomyosin on actin are responsible for this activation (cardiac > slow-skeletal > fast-skeletal). Conversely, at higher Ca2+, addition of fsMyBP-C and cMyBP-C fragments reduced sliding velocities in the in vitro motility assays and increased force production in cardiac muscle fibers. We conclude that due to the high frequency of Ca2+ cycling in cardiac muscle, cardiac MyBP-C may play dual roles at both low and high Ca2+. However, skeletal MyBP-C isoforms may be tuned to meet the needs of specific skeletal muscles.

show abstract

Section: Introductionsupporting

confidence: 72%

“…Previously, thin filament activation by MyBP-C was postulated to prolong relaxation kinetics by promoting the duration of attached cross-bridges 22 . The differential thin filament activation capacity of each MyBP-C isoform regulates contraction, but may also impact relaxation.…”

Section: Resultsmentioning

confidence: 99%

Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner

Lin

Mun

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The regulation of MyBP-C via PTM, and particularly phosphorylation, has been a major focus of several groups (199, 213, 347, 394, 451) (Fig. 9 and Table 8).…”

Section: Myosin Binding Protein-cmentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

View full text Add to dashboard Cite

Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.

show abstract

“…Phosphorylation of cMyBP-C contributes significantly to contractile regulation (Sadayappan et al, 2005 ; Stelzer et al, 2006 ; Gresham et al, 2014 ; Gupta and Robbins, 2014 ; Gresham and Stelzer, 2016 ; Mamidi et al, 2016 ; Moss, 2016 ; Previs et al, 2016 ). Contrary to early studies suggesting that sMyBP-C is not subjected to phosphorylation (Gruen et al, 1999 ), work from our group demonstrated that similar to its cardiac counterpart, sMyBP-C also undergoes phosphorylation (Ackermann and Kontrogianni-Konstantopoulos, 2011a ).…”

Section: Smybp-c: a Complex Sub-family Of Proteins Regulated By Phospmentioning

confidence: 99%

“…The interactions at the NH 2 -terminus of MyBP-C are highly dynamic and regulated via phosphorylation (Figure 1 ; Gruen et al, 1999 ; Sadayappan et al, 2005 ; Shaffer et al, 2009 ; Barefield and Sadayappan, 2010 ). Accordingly, phosphorylation of cMyBP-C within the M-motif accelerates contraction by disrupting binding to myosin, thereby increasing the probability of binding to actin and thus the rate of force development (Sadayappan and de Tombe, 2012 ; Walcott et al, 2015 ; Colson et al, 2016 ; Moss, 2016 ; Previs et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

MYBPC1, an Emerging Myopathic Gene: What We Know and What We Need to Learn

Geist

Kontrogianni‐Konstantopoulos

2016

Front. Physiol.

View full text Add to dashboard Cite

Myosin Binding Protein-C (MyBP-C) comprises a family of accessory proteins that includes the cardiac, slow skeletal, and fast skeletal isoforms. The three isoforms share structural and sequence homology, and localize at the C-zone of the sarcomeric A-band where they interact with thick and thin filaments to regulate the cycling of actomyosin crossbridges. The cardiac isoform, encoded by MYBPC3, has been extensively studied over the last several decades due to its high mutational rate in congenital hypertrophic and dilated cardiomyopathy. It is only recently, however, that the MYBPC1 gene encoding the slow skeletal isoform (sMyBP-C) has gained attention. Accordingly, during the last 5 years it has been shown that MYBPC1 undergoes extensive exon shuffling resulting in the generation of multiple slow variants, which are co-expressed in different combinations and amounts in both slow and fast skeletal muscles. The sMyBP-C variants are subjected to PKA- and PKC-mediated phosphorylation in constitutive and alternatively spliced sites. More importantly, missense, and nonsense mutations in MYBPC1 have been directly linked with the development of severe and lethal forms of distal arthrogryposis myopathy and muscle tremors. Currently, there is no mammalian animal model of sMyBP-C, but new technologies including CRISPR/Cas9 and xenografting of human biopsies into immunodeficient mice could provide unique ways to study the regulation and roles of sMyBP-C in health and disease.

show abstract

Cardiac myosin-binding protein C: A protein once at loose ends finds its regulatory groove

Cited by 10 publications

References 18 publications

Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner

Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner

Thick Filament Protein Network, Functions, and Disease Association

MYBPC1, an Emerging Myopathic Gene: What We Know and What We Need to Learn

Contact Info

Product

Resources

About