Structural Comparison of Ankyrin Repeat Domain of TRPV Channels

Abstract

Transient receptor potential (TRP) channels are tetrameric cation channels involved with sensing of various stimuli from internal and external environments. Six TRPV proteins, TRPV1-6, constitute the vanilloid subfamily of the TRP channel superfamily. TRPV proteins contain six transmembrane segments flanked by two cytoplasmic domains; a large N-terminal domain containing ankyrin repeats and a short C-terminal domain. The N-terminal ankyrin repeat domain (ARD) binds to small molecules and proteins. For example, ATP and calmodulin (CaM) can bind to the ARD and regulate the channel activity of TRPV1, TRPV3 and TRPV4 but not TRPV2, TRPV5, and TRPV6. To date, several structures of TRPV-ARDs have been reported. TRP-ARD structure contains six ankyrin repeats (ANK1 - ANK6) joined with loops (Fingers 1 - 5). To obtain insight into regulatory mechanisms mediated by ATP and CaM binding, structures of the TRPV-ARDs are compared. Structures available include published and unpublished structures of ARDs in the absence or presence of regulatory ligands, as well as structures of ARDs that do not bind these regulatory ligands. Structural comparison showed that Finger 3 in ARD has a large variation in TRPV-ARD structures. Finger 3 is twisted and shrunken in the ATP-bound form of TRPV4-ARD, while it is extended in ATP-free forms of TRPV4-ARD. Finger 3 structures of ATP-bound ARDs (TRPV1 and TRPV4) are similar to those of ARDs that do not bind ATP (TRPV2 and TRPV6). Conserved aromatic residues on Finger 2 might contribute to ATP binding. Interestingly, most mutations causing human genetic diseases in human TRPV4-ARD are located away from ATP binding site, suggesting that additional regulatory interactions and mechanisms exist.