College of Liberal Arts & Sciences

Conformational switching during pH-triggered membrane protein insertion

Tuesday, February 17, 2015

February 17, Tue 2015
1:00 pm, MRB 200 Conference Room

Dr. Alexey Ladokhin

Department of Biochemistry and Molecular Biology, University of Kansas Medical Center

Conformational switching during pH-triggered membrane protein insertion

The conversion of a protein structure from a water-soluble to membrane-inserted form is one of the least understood cellular processes. Examples include the cellular action of various bacterial toxins and colicins, tail-anchor proteins and multiple proteins of the Bcl-2 family, bearing pro-apoptotic and anti-apoptotic functions. In our lab we study diphtheria toxin (DT) T-domain, which undergoes conformational change in response to endosomal acidification, inserts into the lipid bilayer and translocates its own N-terminus and the attached catalytic domain of the toxin across the membrane. Our goal is to describe at the molecular level the mechanisms of pH-triggered conformational switching of the DT T-domain and apoptotic regulator Bcl-xL, which serve as models for membrane insertion/translocation transitions of structurally related proteins. Here we present our progress toward this objective, including structural, kinetic and thermodynamic characterization of the insertion pathway of the DT T-domain and Bcl-xL using both experimental (e.g., Fluorescence Correlation Spectroscopy, Depth-Dependent Fluorescence Lifetime Quenching) and computational approaches (e.g., All-Atom Molecular Dynamics Simulation). Supported by NIH GM069783.

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