The motif of human cardiac myosin-binding protein C is required for its Ca2+-dependent Interaction with calmoduli

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dc.contributor.authorLu, YLen_AU
dc.contributor.authorKwan, AHen_AU
dc.contributor.authorJeffries, CMen_AU
dc.contributor.authorGuss, JMen_AU
dc.contributor.authorTrewhella, Jen_AU
dc.date.accessioned2014-04-27T23:23:10Zen_AU
dc.date.available2014-04-27T23:23:10Zen_AU
dc.date.issued2012-09-07en_AU
dc.date.statistics2014-04-28en_AU
dc.description.abstractThe N-terminal modules of cardiac myosin-binding protein C (cMyBP-C) play a regulatory role in mediating interactions between myosin and actin during heart muscle contraction. The so-called "motif," located between the second and third immunoglobulin modules of the cardiac isoform, is believed to modulate contractility via an "on-off" phosphorylation-dependent tether to myosin Delta S2. Here we report a novel Ca2+-dependent interaction between the motif and calmodulin (CaM) based on the results of a combined fluorescence, NMR, and light and x-ray scattering study. We show that constructs of cMyBP-C containing the motif bind to Ca2+/CaM with a moderate affinity (K-D similar to 10 mu M), which is similar to the affinity previously determined for myosin Delta S2. However, unlike the interaction with myosin Delta S2, the Ca2+/CaM interaction is unaffected by substitution with a triphosphorylated motif mimic. Further, Ca2+/CaM interacts with the highly conserved residues (Glu(319)-Lys(341)) toward the C-terminal end of the motif. Consistent with the Ca2+ dependence, the binding of CaM to the motif is mediated via the hydrophobic clefts within the N- and C-lobes that are known to become more exposed upon Ca2+ binding. Overall, Ca2+/CaM engages with the motif in an extended clamp configuration as opposed to the collapsed binding mode often observed in other CaM-protein interactions. Our results suggest that CaM may act as a structural conduit that links cMyBP-C with Ca2+ signaling pathways to help coordinate phosphorylation events and synchronize the multiple interactions between cMyBP-C, myosin, and actin during the heart muscle contraction. © 2012, American Society for Biochemistry and Molecular Biology.en_AU
dc.identifier.citationLu, Y. L., Kwan, A. H., Jeffries, C. M., Guss, J. M., & Trewhella, J. (2012). The motif of human cardiac myosin-binding protein C is required for its Ca2+-dependent Interaction with calmodulin. Journal of Biological Chemistry, 287(37), 31596-31607. doi:10.1074/jbc.M112.383299en_AU
dc.identifier.govdoc4605en_AU
dc.identifier.issn0021-9258en_AU
dc.identifier.issue37en_AU
dc.identifier.journaltitleJournal of Biological Chemistryen_AU
dc.identifier.pagination31596-31607en_AU
dc.identifier.urihttp://dx.doi.org/10.1074/jbc.M112.383299en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/5496en_AU
dc.identifier.volume287en_AU
dc.language.isoenen_AU
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_AU
dc.subjectCalmodulinen_AU
dc.subjectX-ray lasersen_AU
dc.subjectPhosphotransferasesen_AU
dc.subjectMusclesen_AU
dc.subjectProteinsen_AU
dc.titleThe motif of human cardiac myosin-binding protein C is required for its Ca2+-dependent Interaction with calmodulien_AU
dc.typeJournal Articleen_AU
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