Cryo-Electron Microscopy Reveals Cardiac Myosin Binding Protein-C M-Domain Interactions with the Thin Filament |
| |
| Affiliation: | 1. Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA;2. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA;1. Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN 37831, USA;2. Second Target Station, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN 37831, USA;3. Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892-0520, USA;4. Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892-0520, USA;1. The Center for Biomolecular Therapeutics (CBT), Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;2. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA;3. Biophysics Graduate Program, University of Maryland, College Park, MD 20742, USA;4. Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA;5. Department of Physics, Arizona State University, Tempe, AZ 85287, USA;6. The Institute of Bioscience and Biotechnology Research (IBBR), Rockville, MD 20850, USA;1. Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark;2. Department of Biochemistry and Molecular Biology (BMB), University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark;1. Bavarian NMR Center at the Department of Chemistry, Technical University of Munich, Ernst-Otto-Fischer Strasse 2, 85748 Garching, Germany;2. Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany |
| |
| Abstract: | Cardiac myosin binding protein C (cMyBP-C) modulates cardiac contraction via direct interactions with cardiac thick (myosin) and thin (actin) filaments (cTFs). While its C-terminal domains (e.g. C8-C10) anchor cMyBP-C to the backbone of the thick filament, its N-terminal domains (NTDs) (e.g. C0, C1, M, and C2) bind to both myosin and actin to accomplish its dual roles of inhibiting thick filaments and activating cTFs. While the positions of C0, C1 and C2 on cTF have been reported, the binding site of the M-domain on the surface of the cTF is unknown. Here, we used cryo-EM to reveal that the M-domain interacts with actin via helix 3 of its ordered tri-helix bundle region, while the unstructured part of the M-domain does not maintain extensive interactions with actin. We combined the recently obtained structure of the cTF with the positions of all the four NTDs on its surface to propose a complete model of the NTD binding to the cTF. The model predicts that the interactions of the NTDs with the cTF depend on the activation state of the cTF. At the peak of systole, when bound to the extensively activated cTF, NTDs would inhibit actomyosin interactions. In contrast, at falling Ca2+ levels, NTDs would not compete with the myosin heads for binding to the cTF, but would rather promote formation of active cross-bridges at the adjacent regulatory units located at the opposite cTF strand. Our structural data provides a testable model of the cTF regulation by the cMyBP-C. |
| |
| Keywords: | cardiac myosin binding protein C cardiac muscle regulation thin filament cryo electron microscopy actin binding proteins |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
