Structural Insights into Human cardiac myosin binding protein C and its interaction with Calmodulin — ASN Events
  1. Schedule
  2. Session Twelve - Poster Session D including Happy Hour & Trade Display
  3. Structural Insights into Human cardiac myosin binding protein C and its interaction with Calmodulin

Structural Insights into Human cardiac myosin binding protein C and its interaction with Calmodulin (#430)

Katharine A Michie 1 , Ann H Kwan 1 , Naveed Nadvi 1 , J Mitchell Guss 1 , Jill Trewhella 1
  1. The University of Sydney, Darlington, NSW, Australia

Hypertrophic cardiomyopathy (HCM) is a common disease of the heart muscle (affecting 0.2% of the general population[1]) that can cause sudden cardiac death, often in young athletes with no previous symptoms. 15% of HCM cases are attributed to mutations arising within the gene encoding cardiac Myosin binding protein C[2]

Myosin binding protein C was first identified as a thick filament associated protein in muscle. Alongside its important structural roles, the cardiac isoform (cMyBP-C) has been implicated as an important regulator of contractility. cMyBP-C interacts with many proteins, including actin, myosin and titin and it is comprised of 11 (C0-C10) structural domains – 8 immunoglobulin-like and 3 fibronectin-like. The motif (or m-domain), in the linker between domain C1 and C2, regulates cMyBP-C interactions with actin and myosin via three phosphorylation sites.

Previous work in our laboratory[3] identified that the C-terminal region of the motif (ie downstream of the phosphorylation sites) binds calmodulin with moderate affinity (Kd~10 uM). This result has the biological implication that cMyBP-C/myosin interactions might be linked to the calcium signaling pathway of the cell via calmodulin.

Here we present a further investigation of the cMyBP-C/Calmodulin interaction, with our results suggesting that the calmodulin binding site on cMyBP-C is larger than we first reported, with a higher binding affinity. Our new data include NMR titration experiments, SAXS models of the complex and biochemical experiments assessing binding of calmodulin to cMyBP-C. Finally we present a new NMR structure of the C-terminus of the motif and the entire C2 domain of cMyBP-C. This structure comprises the complete calmodulin binding domain and reveals its relationship to C2.

  1. Maron, B., Gardin, J., Flack, J., Gidding, S., Kurosaki, T. and Bild, D. (1995). Prevalence of hypertrophic cardiomyopathy in a general population of young adults Echocardiographic analysis of 4111 subjects in the CARDIA Study. Circulation, 92(4), pp.785--789.
  2. Niimura, H., Bachinski, L., Sangwatanaroj, S., Watkins, H., Chudley, A., McKenna, W., Kristinsson, A., Roberts, R., Sole, M., Maron, B. and others, (1998). Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. New England Journal of Medicine, 338(18), pp.1248--1257.
  3. Lu, Y., Kwan, A., Jeffries, C., Guss, J. and 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), pp.31596--31607.