2+ Intracellular Ca signaling Kekenes-Huskey, PM. University of Kentucky Probing cellular intracellular calcium signaling and sensing through computation Calcium signaling regulates biological function across a broad range of tissue types and species, 2+ but several factors known to control Ca -dependent signaling ef?ciency have challenged both compu- tational and experimental inquiry. There are signi?cant gaps in our understanding of how nuances in protein structure and dynamics as well as their intracellular distribution affect fundamentally important 2+ processes including how 1) Ca accumulates within localized intracellular regions 2) proteins bind 2+ 2+ Ca with high af?nity 3) Ca 'sensor' proteins regulate signaling cascades. Detailed knowledge about these topics and their inter-dependencies would yield new paradigms in how we view biology, physiology, and health. Computer simulations are attractive in this regard, both for describing phenomena that are dif?cult to directly resolve experimentally, as well as forming integrative conceptual models spanning these underlying topics. However, several prominent hurdles render such transformative simulations cost-prohibitive. Among these, reducing the intractable computational expense involved with model- ing ?ne detail processes like transport governed by sub-nanometer to micron scales, atomistic-scale thermodynamic factors shaping ion/protein binding, and long-range forces that promote protein/protein signaling pathways, is likely the foremost challenge in biophysics today. In this proposal, we outline sev- eral multi-scale algorithmic advances that will ease this challenge, while providing insight into important 2+ Ca -driven processes that orchestrate life: Theme 1 Tuning Ca2+ sensing and response at the molecular level. In this theme, we will develop new paradigms for understanding nature's tricks for controlling speci?city and kinetics in 2+ Ca sensing functions. Theme 2 Automated detection of disease-associated morphological changes in cardiac 2+ cells and their in?uence on Ca homeostasis. In this theme, our lab will leverage troves of underutilized microscopy data to answer questions regarding the role of intracellular organization 2+ in shaping Ca signaling. Theme 3 Molecular mechanisms of cellular-scale control via the P2X4 receptor. In this theme, we will establish strong links between molecular scale protein structure/function and their control of cellular-scale signaling outcomes. 1
2+ Intracellular Ca signaling Kekenes-Huskey, PM. University of Kentucky The key innovation in this proposal are novel computational tools to integrate molecular details of 2+ Ca handling into whole-cell cellular physiology, as well as speci?c hypotheses examining aspects 2+ of molecular through cellular control of Ca -dependent function. These innovations are directly 2+ relevant to human disease, given the pervasive role of Ca in orchestrating cellular physiology and pathophysiology, including muscle contraction, neurological function, immune responses, hormone regulation, and cancer. Successful completion of these studies would lead to new insight into how 2+ Ca signaling is modulated at the subcellular level which affords new insight and motivation to novel strategies to combat human disease. 2
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| Sun, Bin; Cook, Erik C; Creamer, Trevor P et al. (2018) Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin. Biochim Biophys Acta Gen Subj 1862:2651-2659 |
