title: In vivo definition of cardiac myosin-binding protein C's critical interactions with myosin.
abstract: Cardiac myosin-binding protein C (cMyBP-C) is an integral part of the sarcomeric machinery in cardiac muscle that enables normal function. cMyBP-C regulates normal cardiac contraction by functioning as a brake through interactions with the sarcomere's thick, thin, and titin filaments. cMyBP-C's precise effects as it binds to the different filament systems remain obscure, particularly as it impacts on the myosin heavy chain's head domain, contained within the subfragment 2 (S2) region. This portion of the myosin heavy chain also contains the ATPase activity critical for myosin's function. Mutations in myosin's head, as well as in cMyBP-C, are a frequent cause of familial hypertrophic cardiomyopathy (FHC). We generated transgenic lines in which endogenous cMyBP-C was replaced by protein lacking the residues necessary for binding to S2 (cMyBP-C(S2-)). We found, surprisingly, that cMyBP-C lacking the S2 binding site is incorporated normally into the sarcomere, although systolic function is compromised. We show for the first time the acute and chronic in vivo consequences of ablating a filament-specific interaction of cMyBP-C. This work probes the functional consequences, in the whole animal, of modifying a critical structure-function relationship, the protein's ability to bind to a region of the critical enzyme responsible for muscle contraction, the subfragment 2 domain of the myosin heavy chain. We show that the binding is not critical for the protein's correct insertion into the sarcomere's architecture, but is essential for long-term, normal function in the physiological context of the heart.
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA.|Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors: Md Shenuarin
authors: MS
authors: Bhuiyan
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA.
authors: Patrick
authors: P
authors: McLendon
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA.
authors: Jeanne
authors: J
authors: James
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA.
authors: Hanna
authors: H
authors: Osinska
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA.
authors: James
authors: J
authors: Gulick
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA.
authors: Bidur
authors: B
authors: Bhandary
authors: Department of Molecular and Cellular Physiology (J.N.L.), University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
authors: John N
authors: JN
authors: Lorenz
authors: Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children's Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA. jeff.robbins@cchmc.org.
authors: Jeffrey
authors: 0000-0002-3345-5226
authors: J
authors: Robbins
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009119:Muscle Contraction; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D011485:Protein Binding; D012518:Sarcomeres / Q000378:metabolism; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D009218:Myosins; D000099163:Myosin Binding Protein C
keywords: Cardiac; Heart; Myofilament; Myosin; Myosin-binding protein C; Sarcomere