Protein Kinases and Calcium Signaling Proteins
Protein kinases are the molecular time keepers of the cell. By transferring a phosphoryl group onto specific residues, they can nudge an enzyme into overdrive, silence an entire signaling cascade, or finely recalibrate the behavior of a membrane channel. Because phosphorylation touches nearly every physiological process - from the millisecond precision of neuronal firing to the rhythmic contraction of cardiac muscle - the stakes are enormous when these reactions go awry. Mistimed or excessive phosphorylation is increasingly recognized as a root cause of neurodegeneration, cancer, and inherited heart disease. Our laboratory asks how understudied kinases and calcium sensing proteins shape the function of ion channels and adaptor proteins at neuronal, muscular, and neuromuscular junctions. By focusing on gatekeepers such as NaV1.5 and NaV1.7, we aim to understand how phosphorylation and Ca²⁺ signals converge to control electrical excitability and how their mis-regulation leads to pain syndromes or arrhythmias. To uncover these mechanisms we blend complementary, high precision biophysical techniques. X ray crystallography and single particle cryo electron microscopy reveal atomic level snapshots of kinases and ion channel complexes, while isothermal titration calorimetry dissects the thermodynamic forces that drive their interactions. Binding kinetics and affinities are captured with bio layer interferometry and microscale thermophoresis, and circular dichroism spectroscopy safeguards the structural integrity of engineered mutants. Enzymatic assays, both radioactive and fluorescence coupled, translate these structural insights into quantitative measures of catalytic efficiency and inhibitor potency, completing a rigorous structure-function loop. Our long term objective is to turn fundamental understanding into practical benefits. High resolution structures highlight hidden allosteric pockets for structure based drug design, and detailed energetic maps guide the creation of site directed mutants and designer peptides that modulate kinase or channel activity with surgical precision. By marrying structural snapshots to quantitative biophysics, we aim to provide blueprints for next generation therapeutics that restore balanced phosphorylation and calcium signaling in disorders of the nervous system, heart, and skeletal muscle.