Structure and Function of the Epithelial Calcium Channel TRPV6

Abstract

Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca2+-selective TRP channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca2+ uptake channels in epithelial tissues. We solved the crystal structure of rat TRPV6 at 3.25 Å resolution. The overall architecture of TRPV6 reveals shared and unique features compared to other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular “skirt” involved in allosteric modulation. In the K+ channel-like transmembrane domain, Ca2+ selectivity is determined by direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter. Based on crystallographically identified cation binding sites at the pore axis and extracellular vestibule, we propose a model for the Ca2+ permeation mechanism. We also show that mutations in the transmembrane domain of TRPV6 can convert the arrangement of the S1-S4 and pore domains from swapped to non-swapped, raising the possibility that these channels can fold into either arrangement in vivo. Our results provide a structural foundation to understand the regulation of epithelial Ca2+ uptake and its role in normal and disease states.