Biology

Dr. Appu K Singh
Department of Biochemistry and Molecular Biophysics, Columbia University, New York 10032, USA

Abstract: 

TRPV6 channels belong to the transient receptor potential (TRP) superfamily of ion channels that play a key role in Ca²⁺ homeostasis as Ca²⁺ entry channels in epithelial cells. Aberrant expression of TRPV6 is implicated in development and progression of numerous forms of cancer such as prostate cancer, breast cancer, and its overexpression pattern correlates with the aggressiveness of the disease. Consequently, TRPV6 has recently emerged as a prognosis marker and a potential target for treatment of various carcinomas. We used structural and functional studies to comprehensively understand the molecular principles underlying calcium selectivity, activation and inactivation mechanism of TRPV6. We have shown that a ring of four aspartate residues in selectivity filter encodes unique calcium selectivity of TRPV6, and its permeation follows a “knock off” mechanism. Furthermore, we demonstrated that activation mechanism of TRPV6 is markedly different from other tetrameric ion channels and is accompanied by dramatic conformation changes in the pore lining helices that undergo an α to π transition at alanine hinge below the selectivity filter. Altogether, our results provide a structural foundation to understand the regulation of epithelial Ca²⁺ uptake. I will discuss the implications of these results in the context of calcium homeostasis and associated pathophysiology.