title: Species-specific differences in the Pro-Ala rich region of cardiac myosin binding protein-C.
abstract: Cardiac myosin binding protein-C (cMyBP-C) is an accessory protein found in the A-bands of vertebrate sarcomeres and mutations in the cMyBP-C gene are a leading cause of familial hypertrophic cardiomyopathy. The regulatory functions of cMyBP-C have been attributed to the N-terminus of the protein, which is composed of tandem immunoglobulin (Ig)-like domains (C0, C1, and C2), a region rich in proline and alanine residues (the Pro-Ala rich region) that links C0 and C1, and a unique sequence referred to as the MyBP-C motif, or M-domain, that links C1 and C2. Recombinant proteins that contain various combinations of the N-terminal domains of cMyBP-C can activate actomyosin interactions in the absence of Ca(2+), but the specific sequences required for these effects differ between species; the Pro-Ala region has been implicated in human cMyBP-C whereas the C1 and M-domains appear important in mouse cMyBP-C. To investigate whether species-specific differences in sequence can account for the observed differences in function, we compared sequences of the Pro-Ala rich region in cMyBP-C isoforms from different species. Here we report that the number of proline and alanine residues in the Pro-Ala rich region varies significantly between different species and that the number correlates directly with mammalian body size and inversely with heart rate. Thus, systematic sequence differences in the Pro-Ala rich region of cMyBP-C may contribute to observed functional differences in human versus mouse cMyBP-C isoforms and suggest that the Pro-Ala region may be important in matching contractile speed to cardiac function across species.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA, USA. jfshaffer@ucdavis.edu
authors.forename: Justin F
authors.initials: JF
authors.lastname: Shaffer
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Harris
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry*; D006321:Heart / Q000502:physiology*; D006801:Humans; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D004151:Dipeptides; D011994:Recombinant Proteins; D000099163:Myosin Binding Protein C; C038123:alanylproline