Molecular Underpinning of Postsynaptic Calmodulin-dependent Calcium Signaling

When: Monday, May 8, 2017
Where: PGH 563
Time: 11:00 AM – Noon

Speaker: Prof. Margaret Cheung, University of Houston

Host: Dr. Edgar Gabriel

Calcium (Ca²⁺) is exquisitely utilized by a cell for transducing external stimuli through its gradient of extracellular (~1000 μM) and intracellular (~0.1 μM) concentration. A broad spectrum of Ca²⁺ signals are encoded by protein calmodulin (CaM) through specific binding with various targets regulating CaM-dependent Ca2+ signaling pathways in neurons. I will focus on binding between CaM and two specific targets, Ca²⁺/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they antagonistically regulate CaM-dependent Ca²⁺ signaling pathways in neurons. I will show the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca²⁺) by integrating coarse-grained models and all-atomistic simulations with non-equilibrium physics. We discovered the molecular underpinnings of lowered affinity of Ca²⁺ for CaM in the presence of Ng by showing that the N-terminal acidic region of Ng peptide pries open the β-sheet structure between the Ca²⁺ binding loops particularly at C-domain of CaM, enabling Ca²⁺ release. In contrast, CaMKII peptide increases Ca²⁺ affinity for the C-domain of CaM by stabilizing the two Ca²⁺ binding loops. Through distinctive structural differences in the bound complexes of apoCaM-Ng_13-49 and holoCaM-CaMKII, CaM’s affinity for Ca²⁺ is delineated by its progressive mechanism of target binding. I will discuss them in the context of evolution and in the crowded environment.

Bio:

Margaret Cheung is an Associate Professor of Physics at the University of Houston. She graduated from the National Taiwan University with a bachelor’s degree in chemistry and received her Ph.D. in physics from the University of California, San Diego. She carried out theoretical biological physics and bioinformatics research as a Sloan Postdoctoral Fellow at the University of Maryland and started her lab at the University of Houston in 2006. Professor Cheung’s research is in the field of protein folding inside a cell, calmodulin dependent calcium signaling, and quantum efficiency in artificial photosynthetic materials. She is particularly interested in developing coarse-grained models for protein dynamics in crowded systems, creating multiphysics models that bridge dynamics across wide temporal and spatial scales, and designing computational algorithms that effectively integrate novel high-performance resources. These systems can then be applied for understanding of biological function and for developing therapeutic strategies. She is a fellow of the American Physical Society and a Senior Scientist at the NSF-funded Center for Theoretical Biological Physics at Rice University.