Thu. March 7, 3:24 p.m. – 3:36 p.m. CST
103C
Calmodulin (CaM) is the main calcium (Ca2+) binding protein that transduces the calcium signal to numerous downstream proteins including Ca2+-CaM dependent protein kinase II (CaMKII). The affinity of CaM for CaMKII increases by over 3000-fold as Ca2+ binds to CaM and in turn the affinity of Ca2+ for CaM increases by many folds as a result of CaM interactions with CaMKII. This reciprocal effect between Ca2+, CaM, and CaMKII has been shown by many research groups; however, the basic mechanism underlying such complex process is still not well understood. In this work, we used the experimental and non-equilibrium coarse-grained molecular dynamics simulations to study the dynamics of CaM and its interactions with a family of three peptides (wildtype, 1-residue mutation, and 3-residue mutation) from the CaM-binding domain of CaMKII. Our results show that CaM interactions with CaMKIIp (wildtype and 1-residue mutation) lead to a large increase in Ca2+ affinity for CaM whereas CaM interactions with CaMKIIp (3-residue mutation) show over 50-fold decrease in Ca2+ affinity for CaM relative to the wildtype. Additionally, these differences occur specifically in the C-domain of CaM, where the Ca2+ binding sites are highly disturbed for the CaM/CaMKII (3-residue mutation). These observations highlight the contribution of specific residues, 296-RRK-298, of the wildtype peptide to the high Ca2+ affinity for CaM. We then propose that residues 296-RRK-298 of the peptide interact with the negatively charged residues in the Ca2+ binding sites of the C-domain of CaM through electrostatic interactions which lead to the reduced Ca2+ release rate from the C-domain of CaM.
Presented By
- Jules Berlin Nde Kengne (University of Washington)
Authors
- Jules Berlin Nde Kengne (University of Washington)
- Pengzhi Zhang (Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute)
- Neal Waxham (3Department of Neurobiology and Anatomy, University of Texas Health Science Center)
- Margaret S Cheung (Pacific Northwest National Laboratory)