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Research Interests

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This laboratory probes the linkage between cooperative ligand binding, conformational change and enzyme activation by calmodulin, a regulatory calcium- binding protein. Calmodulin is the primary eukaryotic intracellular calcium receptor and serves as a second messenger to regulate cellular responses to transient calcium fluxes. It is clinically relevant for human physiology (for example, it is a target of anti-psychotic drugs) and is also found in plants and fungi. Cooperative binding of four calcium ions to calmodulin causes large conformational changes; these changes control the sites and extent of calmodulin activation of important cellular enzymes and structural proteins (see Figure).

In order to determine the states that are functionally significant in this complex network of interactions, it is necessary to develop and apply new methods to directly determine energetic and structural properties of calcium binding. Quantitative proteolytic footprinting and applications of multi-dimensional heteronuclear NMR are capable of monitoring individual residues or bonds during a titration representative of a cellular influx of calcium. These studies have shown that the two domains of calmodulin interact in different ways as calcium fills the four sites of the protein.

Calcium-dependent structural rearrangements of calmodulin also are monitored by changes in the fluorescence, circular dichroism and hydrodynamic properties. These combined approaches are aimed at elucidating molecular mechanisms of cooperativity in calmodulin by determining the differences in intrinsic binding affinity at the four calcium-binding sites of calmodulin and the extent and nature of inter- and intra-domain cooperativity. To dissect these interactions, we are studying the isolated domains of calmodulin and many mutants shown to have phenotypic effects on complexes of calmodulin with its target enzymes.

Computational molecular modeling is used to visualize and calculate properties of these proteins and serves as a complement to the experimental studies of ligand- linked conformational change. The goal is to combine energetic and structural data to formulate models that will explain how synchronized changes in calcium levels modulate many diverse physiological processes.

Events

Biology Seminar: "Molecular control of meiotic chromosome dynamics" promotional image

Biology Seminar: "Molecular control of meiotic chromosome dynamics"

Friday, September 19, 2025 3:30pm
Biology Building East
The Department of Biology’s seminar speaker on Friday, Sept. 19, at 3:30pm is Yumi Kim, an Associate Professor in the Department of Biology at Johns Hopkins University. Her seminar will be held in Kollros Auditorium (Room 101), Biology Building East (BBE). Sarit Smolikove is the faculty host. A reception with refreshments will be held in the BBE Lobby following the seminar.
College of Pharmacy PSET Seminar Series: Mara Steinkamp, PhD promotional image

College of Pharmacy PSET Seminar Series: Mara Steinkamp, PhD

Tuesday, September 23, 2025 11:30am
College of Pharmacy Building
The Department of Pharmaceutical Sciences and Experimental Therapeutics (PSET) in the College of Pharmacy will host a seminar presented by: Mara Steinkamp, PhDAssistant ProfessorDepartment of PathologyUniversity of New MexicoAlbuquerque, New MexicoSeminar Title: "Advancing Humanized PDX Mouse Models of Gynecological Cancer for Preclinical Immunotherapy Testing"All are welcome to attend. No pre-registration required.
College of Pharmacy PSET Seminar Series: Guohua An, MD, PhD promotional image

College of Pharmacy PSET Seminar Series: Guohua An, MD, PhD

Tuesday, September 30, 2025 11:30am
College of Pharmacy Building
The Department of Pharmaceutical Sciences and Experimental Therapeutics (PSET) in the College of Pharmacy will host a seminar presented by: Guohua An, MD, PhDAssociate ProfessorDepartment of Pharmaceutical Sciences and Experimental TherapeuticsUniversity of IowaIowa City, IowaSeminar Title: "Pharmacometric Modeling in Drug Development, Clinical Care, and Pharmaceutical Research"All are welcome to attend. No pre-registration required.