CALMODULIN-DEPENDENT CALCIUM SIGNALING

Cells must signal to adapt to a changing environment. Calcium (Ca2+) signaling requires Ca2+ as a messenger whose concentration varies with time. Calmodulin (CaM) is an evolutionarily conserved Ca2+-binding protein for decoding the Ca2+ signal in all eukaryotic cells, which selectively activates distinctive targets in downstream pathways. However, its Ca2+-binding properties alone appear insufficient to decode rapidly fluctuating Ca2+ signals. We are testing the hypothesis that the interaction between CaM and its targets directly tunes the Ca2+-binding properties of CaM through reciprocal interactions mediated by conformational adjustments. We apply methods of quantum mechanics, statistical physics, physical modeling, and machine learning to understand the molecular mechanism of target binding and selection in CaM-dependent Ca2+ signaling pathways. We are currently interested in developing force fields for calcium ions and coarse-grained models for CaM and its binding targets. We show that the conformations of CaM and its target must both undergo gross structural changes to form a bound complex. The structural variation of a bound complex depends on the feature of a target that influences the stability of Ca2+ -binding loops. This binary complex reveals unique binding affinity for Ca2+ which does not exist in CaM alone.

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  Calmodulin-dependent Calcium Signaling

Q. Wang, P. Zhang, L. Hoffman, S. Tripathi, D. Homouz, L. Y., N. M. Waxham and M. S. Cheung, Proc Nat Acad Sci USA. 110, 20545-20550 (2013).

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Lessons in protein design from combined evolution and conformational dynamics

S. Tripathi, M. N. Waxham, M. S. Cheung and Y. Liu, Sci. Reports 5, 14259 (2015).

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Opposing intermolecular tuning of Ca2+ affinity for calmoduin by Neurogranin and CaMKII peptides

  P. Zhang, S. Tripathi, H. Trinh, M. S. Cheung, Biophysical Journal. 112, 1105–1119 (2017).