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Phosphorylation switches specific for the cardiac isoform of myosin binding protein‐C: a modulator of cardiac contraction?
Author(s) -
Gautel M.,
Zuffardi O.,
Freiburg A.,
Labeit S.
Publication year - 1995
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1995.tb07187.x
Subject(s) - gene isoform , biology , phosphorylation , myosin , microbiology and biotechnology , biochemistry , gene
Cardiac myosin binding protein‐C (cardiac MyBP‐C, cardiac C protein) belongs to a family of proteins implicated in both regulatory and structural functions of striated muscle. For the cardiac isoform, regulatory phosphorylation in vivo by cAMP‐dependent protein kinase (PKA) upon adrenergic stimulation is linked to modulation of cardiac contraction. The sequence of human cardiac MyBP‐C now reveals regulatory motifs specific for this isoform. Site‐directed mutagenesis identifies a LAGGGRRIS loop in the N‐terminal region of cardiac MyBP‐C as the key substrate site for phosphorylation by both PKA and a calmodulin‐dependent protein kinase associated with the native protein. Phosphorylation of two further sites by PKA is induced by phosphorylation of this isoform‐specific site. This phosphorylation switch can be mimicked by aspartic acid instead of phosphoserine. Cardiac MyBP‐C is therefore specifically equipped with sensors for adrenergic regulation of cardiac contraction, possibly implicating cardiac MyBP‐C in cardiac disease. The gene coding for cardiac MyBP‐C has been assigned to the chromosomal location 11p11.2 in humans, and is therefore in a region of physical linkage to subsets of familial hypertrophic cardiomyopathy (FHC). This makes cardiac MyBP‐C a candidate gene for chromosome 11‐associated FHC.