pH sensitivity in talin

CHED 237

Dinah Zaghi, dinahzaghi@yahoo.com1, Matthew P. Jacobson, matt.jacobson@ucsf.edu2, and Gabriela Barreiro, gabriela.barreiro@gmail.com2. (1) Department of Chemistry, Stern College for Women, 245 Lexington Avenue, New York, NY 10016, (2) Department of Pharmaceutical Chemistry, University of California, San Francisco, UCSF MC 2240, 600 16th Street, San Francisco, CA 94158-2517
Studies show that cells can use intracellular pH to regulate actin-based motility. At a molecular level we discovered a correlation between pH changes and the structure of talin, an actin binding protein. Computational methods were used to investigate a homology model of the C terminal region in the I/LWEQ domain of the structure HIP1R. In the five helices, five side chains were predicted to have pKa's near a physiological pH. A histidine and four aspartic or glutamic acids with strongly shifted pKa's were all clustered at one end. Constant-pH molecular dynamic simulations revealed protonation states between pH 6 and 7.5 and the protein's conformational changes, allowing the residues to functions as pH sensors. In correlation with experimental results, at a higher pH the first helix, otherwise known as the USH, traveled away from the other helices, exposing a “cryptic” binding site.