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.

中文翻译：

---

人类 TRPV6 祖先和衍生单倍型的结构-功能分析


TRPV6 是一种 Ca²⁺ 选择性通道，可介导肠道对钙的摄取，并有助于人类癌症的发生和发展。TRPV6 由祖先和衍生的单倍型表示，它们以三个非同义多态性不同，分别位于 N 末端锚蛋白重复结构域 （C157R）、S1-S2 细胞外环 （M378V） 和 C 端 （M681T）。祖先和衍生的单倍型被提议作为基因组因子，导致非洲血统的癌症患者出现不同的结果。我们解决了在开放和钙调蛋白 （CaM） 结合的灭活状态下祖先和衍生的 TRPV6 的冷冻电子显微镜 （cryo-EM） 结构。两种状态都未显示出由非同义多态性引起的实质性结构差异。通过电生理记录和 Ca²⁺ 摄取测量评估的功能特性，以及通过分子建模评估的水和离子渗透性在单倍型之间也似乎相似。因此，祖先和衍生的 TRPV6 具有相似的结构和功能，这意味着其他因素是导致癌症易感性差异的原因。