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Myosin binding protein C: implications for signal-transduction.

Knöll R - J. Muscle Res. Cell. Motil. (2011)

Bottom Line: While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood.However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play.Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Imperial College, National Heart and Lung Institute, British Heart Foundation-Centre for Research Excellence, Myocardial Genetics, London, UK. r.knoell@imperial.ac.uk

ABSTRACT
Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

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Related in: MedlinePlus

Depicts the structure of MYBPC3 as well as highlights important structural domains and indicates MYBPC3 interacting proteins. Please note: the number of phosphorylation sites localized in the MYBPC motif is species dependent. Ig immunoglobulin, P/A proline/alanine, Fn fibronectin)
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Fig2: Depicts the structure of MYBPC3 as well as highlights important structural domains and indicates MYBPC3 interacting proteins. Please note: the number of phosphorylation sites localized in the MYBPC motif is species dependent. Ig immunoglobulin, P/A proline/alanine, Fn fibronectin)

Mentions: Myosin binding protein C (also known as C-protein: MyBP-C; cardiac isoform abbreviated: cMyBP-C) was discovered in 1973 (Offer et al. 1973) and is located on 7–9 stripes of 43 nm spacing in each half of the A-band (cross bridge bearing zone, C-region) of the sarcomere in skeletal and cardiac muscles (Fig. 1). To date three different MYBPC proteins are known, each encoded by different genes (MYBPC 1–3), where slow (MYBPC1, 1141 aa) and fast (MYBPC2 1141 aa) twitch muscle isoforms are restricted to skeletal muscle tissues and whereas MYBPC3 (1273 aa) is expressed exclusively in cardiac myocytes (Furst et al. 1992; Gautel et al. 1995; Weber et al. 1993). All MYBPC molecules share common architectural features: they are composed of seven immunoglobulin domains (Ig) and three fibronectin type III domains (FnIII) called C1–10 where a 105 amino acid myosin binding protein motif is localized between C1 and C2. In addition, a proline and alanine rich (PA) domain is localized near the aminoterminus (Fig. 2). Domains C9–C10 interact with titin and C10 interacts with light meromyosin (LMM) (Freiburg and Gautel 1996). The actin and S2 (head region) myosin heavy chain binding regions are located at the aminoterminus (Fig. 2). Skeletal muscle MYBPC also interacts with nebulin, but this interaction is not well studied (Jin and Wang 1991) (for a review (Kontrogianni-Konstantopoulos et al. 2009)). Also the MYBPC1-variant 1 interacts with the giant protein obscurin (Ackermann et al. 2009). Another novel interaction between the cardiac specific C0 domain and the regulatory light chain (RLC) has been analyzed by Ratti et al. (2011).Fig. 1


Myosin binding protein C: implications for signal-transduction.

Knöll R - J. Muscle Res. Cell. Motil. (2011)

Depicts the structure of MYBPC3 as well as highlights important structural domains and indicates MYBPC3 interacting proteins. Please note: the number of phosphorylation sites localized in the MYBPC motif is species dependent. Ig immunoglobulin, P/A proline/alanine, Fn fibronectin)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351598&req=5

Fig2: Depicts the structure of MYBPC3 as well as highlights important structural domains and indicates MYBPC3 interacting proteins. Please note: the number of phosphorylation sites localized in the MYBPC motif is species dependent. Ig immunoglobulin, P/A proline/alanine, Fn fibronectin)
Mentions: Myosin binding protein C (also known as C-protein: MyBP-C; cardiac isoform abbreviated: cMyBP-C) was discovered in 1973 (Offer et al. 1973) and is located on 7–9 stripes of 43 nm spacing in each half of the A-band (cross bridge bearing zone, C-region) of the sarcomere in skeletal and cardiac muscles (Fig. 1). To date three different MYBPC proteins are known, each encoded by different genes (MYBPC 1–3), where slow (MYBPC1, 1141 aa) and fast (MYBPC2 1141 aa) twitch muscle isoforms are restricted to skeletal muscle tissues and whereas MYBPC3 (1273 aa) is expressed exclusively in cardiac myocytes (Furst et al. 1992; Gautel et al. 1995; Weber et al. 1993). All MYBPC molecules share common architectural features: they are composed of seven immunoglobulin domains (Ig) and three fibronectin type III domains (FnIII) called C1–10 where a 105 amino acid myosin binding protein motif is localized between C1 and C2. In addition, a proline and alanine rich (PA) domain is localized near the aminoterminus (Fig. 2). Domains C9–C10 interact with titin and C10 interacts with light meromyosin (LMM) (Freiburg and Gautel 1996). The actin and S2 (head region) myosin heavy chain binding regions are located at the aminoterminus (Fig. 2). Skeletal muscle MYBPC also interacts with nebulin, but this interaction is not well studied (Jin and Wang 1991) (for a review (Kontrogianni-Konstantopoulos et al. 2009)). Also the MYBPC1-variant 1 interacts with the giant protein obscurin (Ackermann et al. 2009). Another novel interaction between the cardiac specific C0 domain and the regulatory light chain (RLC) has been analyzed by Ratti et al. (2011).Fig. 1

Bottom Line: While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood.However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play.Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Imperial College, National Heart and Lung Institute, British Heart Foundation-Centre for Research Excellence, Myocardial Genetics, London, UK. r.knoell@imperial.ac.uk

ABSTRACT
Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure.

Show MeSH
Related in: MedlinePlus