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Axial distribution of myosin binding protein-C is unaffected by mutations in human cardiac and skeletal muscle.

Vydyanath A, Gurnett CA, Marston S, Luther PK - J. Muscle Res. Cell. Motil. (2012)

Bottom Line: Myosin binding protein-C (MyBP-C), a major thick filament associated sarcomeric protein, plays an important functional and structural role in regulating sarcomere assembly and crossbridge formation.Due to the difficulty of obtaining normal human tissue, we compared the distribution to the A-band structure in normal frog skeletal, rat cardiac muscle and in cardiac muscle of MyBP-C-deficient mice.Very similar overall profile averages were obtained from the C-zones in cardiac HCM samples and skeletal DA-1 samples with MyBP-C gene mutations, suggesting that mutations in MyBP-C do not alter its mean axial distribution along the thick filament.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK. a.vydyanath@imperial.ac.uk

ABSTRACT
Myosin binding protein-C (MyBP-C), a major thick filament associated sarcomeric protein, plays an important functional and structural role in regulating sarcomere assembly and crossbridge formation. Missing or aberrant MyBP-C proteins (both cardiac and skeletal) have been shown to cause both cardiac and skeletal myopathies, thereby emphasising its importance for the normal functioning of the sarcomere. Mutations in cardiac MyBP-C are a major cause of hypertrophic cardiomyopathy (HCM), while mutations in skeletal MyBP-C have been implicated in a disease of skeletal muscle-distal arthrogryposis type 1 (DA-1). Here we report the first detailed electron microscopy studies on human cardiac and skeletal tissues carrying MyBP-C gene mutations, using samples obtained from HCM and DA-1 patients. We have used established image averaging methods to identify and study the axial distribution of MyBP-C on the thick filament by averaging profile plots of the A-band of the sarcomere from electron micrographs of human cardiac and skeletal myopathy specimens. Due to the difficulty of obtaining normal human tissue, we compared the distribution to the A-band structure in normal frog skeletal, rat cardiac muscle and in cardiac muscle of MyBP-C-deficient mice. Very similar overall profile averages were obtained from the C-zones in cardiac HCM samples and skeletal DA-1 samples with MyBP-C gene mutations, suggesting that mutations in MyBP-C do not alter its mean axial distribution along the thick filament.

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Organisation of MyBP-C. a Schematic showing the domain architecture of cardiac and skeletal MyBP-C. The protein is composed of repeats of IgI-like and FnIII-like domains. PA-domain refers to the proline–alanine rich linker region while M-domain refers to the 105 residue domain between C1 and C2 also called MyBP-C motif. b Schematic arrangement of cardiac MyBP-C (cMyBP-C) with respect to the components of the sarcomere. Here the C-terminal of cMyBP-C is arranged parallel to the thick filament backbone (Squire et al. 2003), while the N-terminal is shown interacting with a thin filament
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Fig1: Organisation of MyBP-C. a Schematic showing the domain architecture of cardiac and skeletal MyBP-C. The protein is composed of repeats of IgI-like and FnIII-like domains. PA-domain refers to the proline–alanine rich linker region while M-domain refers to the 105 residue domain between C1 and C2 also called MyBP-C motif. b Schematic arrangement of cardiac MyBP-C (cMyBP-C) with respect to the components of the sarcomere. Here the C-terminal of cMyBP-C is arranged parallel to the thick filament backbone (Squire et al. 2003), while the N-terminal is shown interacting with a thin filament

Mentions: Myosin binding protein-C (MyBP-C) is a 140 kDa sarcomeric protein that binds to the thick filament in vertebrate striated muscle and can be visualised as 7–9 stripes of separation 43 nm in the C-zone of the sarcomere. It was discovered in skeletal muscle nearly 40 years ago by Offer et al. (1973) as a contaminant in the preparation of purified myosin. There are three isoforms, slow skeletal, fast skeletal and cardiac, encoded by the genes MYBPC1, MYBPC2 and MYBPC3 and located on chromosome 12, 19 and 11 respectively (for reviews see Flashman et al. 2004; Harris et al. 2011; Schlossarek et al. 2011). All three isoforms share a conserved domain architecture, composed of seven immunoglobulin (IgI) domains and three fibronectin type III (FnIII) domains depicted as C1–C10 (Fig. 1a), with a 105 residue domain between C1 and C2 called the M-domain or MyBP-C motif and a proline- and alanine-rich region near the N-terminus (Gautel et al. 1995; Okagaki et al. 1993). The cardiac isoform differs from the skeletal isoform in three major ways: it has an additional Ig domain, C0, at the N-terminus; it has 3 phosphorylation sites in the M-domain and the domain C5 has a proline-rich 25 residue insertion (Gautel et al. 1995). The homology of the amino acids in all three isoforms is high, with 39.6 % sequence identity in the human isoforms.Fig. 1


Axial distribution of myosin binding protein-C is unaffected by mutations in human cardiac and skeletal muscle.

Vydyanath A, Gurnett CA, Marston S, Luther PK - J. Muscle Res. Cell. Motil. (2012)

Organisation of MyBP-C. a Schematic showing the domain architecture of cardiac and skeletal MyBP-C. The protein is composed of repeats of IgI-like and FnIII-like domains. PA-domain refers to the proline–alanine rich linker region while M-domain refers to the 105 residue domain between C1 and C2 also called MyBP-C motif. b Schematic arrangement of cardiac MyBP-C (cMyBP-C) with respect to the components of the sarcomere. Here the C-terminal of cMyBP-C is arranged parallel to the thick filament backbone (Squire et al. 2003), while the N-terminal is shown interacting with a thin filament
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351610&req=5

Fig1: Organisation of MyBP-C. a Schematic showing the domain architecture of cardiac and skeletal MyBP-C. The protein is composed of repeats of IgI-like and FnIII-like domains. PA-domain refers to the proline–alanine rich linker region while M-domain refers to the 105 residue domain between C1 and C2 also called MyBP-C motif. b Schematic arrangement of cardiac MyBP-C (cMyBP-C) with respect to the components of the sarcomere. Here the C-terminal of cMyBP-C is arranged parallel to the thick filament backbone (Squire et al. 2003), while the N-terminal is shown interacting with a thin filament
Mentions: Myosin binding protein-C (MyBP-C) is a 140 kDa sarcomeric protein that binds to the thick filament in vertebrate striated muscle and can be visualised as 7–9 stripes of separation 43 nm in the C-zone of the sarcomere. It was discovered in skeletal muscle nearly 40 years ago by Offer et al. (1973) as a contaminant in the preparation of purified myosin. There are three isoforms, slow skeletal, fast skeletal and cardiac, encoded by the genes MYBPC1, MYBPC2 and MYBPC3 and located on chromosome 12, 19 and 11 respectively (for reviews see Flashman et al. 2004; Harris et al. 2011; Schlossarek et al. 2011). All three isoforms share a conserved domain architecture, composed of seven immunoglobulin (IgI) domains and three fibronectin type III (FnIII) domains depicted as C1–C10 (Fig. 1a), with a 105 residue domain between C1 and C2 called the M-domain or MyBP-C motif and a proline- and alanine-rich region near the N-terminus (Gautel et al. 1995; Okagaki et al. 1993). The cardiac isoform differs from the skeletal isoform in three major ways: it has an additional Ig domain, C0, at the N-terminus; it has 3 phosphorylation sites in the M-domain and the domain C5 has a proline-rich 25 residue insertion (Gautel et al. 1995). The homology of the amino acids in all three isoforms is high, with 39.6 % sequence identity in the human isoforms.Fig. 1

Bottom Line: Myosin binding protein-C (MyBP-C), a major thick filament associated sarcomeric protein, plays an important functional and structural role in regulating sarcomere assembly and crossbridge formation.Due to the difficulty of obtaining normal human tissue, we compared the distribution to the A-band structure in normal frog skeletal, rat cardiac muscle and in cardiac muscle of MyBP-C-deficient mice.Very similar overall profile averages were obtained from the C-zones in cardiac HCM samples and skeletal DA-1 samples with MyBP-C gene mutations, suggesting that mutations in MyBP-C do not alter its mean axial distribution along the thick filament.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK. a.vydyanath@imperial.ac.uk

ABSTRACT
Myosin binding protein-C (MyBP-C), a major thick filament associated sarcomeric protein, plays an important functional and structural role in regulating sarcomere assembly and crossbridge formation. Missing or aberrant MyBP-C proteins (both cardiac and skeletal) have been shown to cause both cardiac and skeletal myopathies, thereby emphasising its importance for the normal functioning of the sarcomere. Mutations in cardiac MyBP-C are a major cause of hypertrophic cardiomyopathy (HCM), while mutations in skeletal MyBP-C have been implicated in a disease of skeletal muscle-distal arthrogryposis type 1 (DA-1). Here we report the first detailed electron microscopy studies on human cardiac and skeletal tissues carrying MyBP-C gene mutations, using samples obtained from HCM and DA-1 patients. We have used established image averaging methods to identify and study the axial distribution of MyBP-C on the thick filament by averaging profile plots of the A-band of the sarcomere from electron micrographs of human cardiac and skeletal myopathy specimens. Due to the difficulty of obtaining normal human tissue, we compared the distribution to the A-band structure in normal frog skeletal, rat cardiac muscle and in cardiac muscle of MyBP-C-deficient mice. Very similar overall profile averages were obtained from the C-zones in cardiac HCM samples and skeletal DA-1 samples with MyBP-C gene mutations, suggesting that mutations in MyBP-C do not alter its mean axial distribution along the thick filament.

Show MeSH
Related in: MedlinePlus