Please use this identifier to cite or link to this item: https://apo.ansto.gov.au/dspace/handle/10238/5496
Title: The motif of human cardiac myosin-binding protein C is required for its Ca2+-dependent Interaction with calmoduli
Authors: Lu, YL
Kwan, AH
Jeffries, CM
Guss, JM
Trewhella, J
Keywords: Calmodulin
X-ray lasers
Phosphotransferases
Muscles
Proteins
Issue Date: 7-Sep-2012
Publisher: American Society for Biochemistry and Molecular Biology
Citation: Lu, 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.M112.383299
Abstract: The 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.
Gov't Doc #: 4605
URI: http://dx.doi.org/10.1074/jbc.M112.383299
http://apo.ansto.gov.au/dspace/handle/10238/5496
ISSN: 0021-9258
Appears in Collections:Journal Articles

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