Structure-function analyses of human TRPV6 ancestral and derived haplotypes

Structure. 2025. Vol. 33. No. 1. P. 91–103.e5.

Neuberger A., Shalygin A., Trofimov Y. A., Veretenenko I. I., Nadehzdin K. D., Krylov N. A., Gudermann T., Efremov R., Chubanov V., Sobolevsky A. I.

TRPV6 is a Ca2+ selective channel that mediates calcium uptake in the gut and contributes to the development
and progression of human cancers. TRPV6 is represented by the ancestral and derived haplotypes
that differ by three non-synonymous polymorphisms, located in the N-terminal ankyrin repeat domain
(C157R), S1–S2 extracellular loop (M378V), and C-terminus (M681T). The ancestral and derived haplotypes
were proposed to serve as genomic factors causing a different outcome for cancer patients of African
ancestry. We solved cryoelectron microscopy (cryo-EM) structures of ancestral and derived TRPV6 in
the open and calmodulin (CaM)-bound inactivated states. Neither state shows substantial structural differences
caused by the non-synonymous polymorphisms. Functional properties assessed by electrophysiological
recordings and Ca2+ uptake measurements, and water and ion permeation evaluated by molecular
modeling also appear similar between the haplotypes. Therefore, ancestral and derived TRPV6 have similar
structure and function, implying that other factors are responsible for the differences in susceptibility to
cancer.

Keywords: молекулярная динамика, protein structure, структура белка, Ионные каналы, ion channels, molecular dynamics, cryo-EM, крио-ЭМ