National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM103899
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM129357
米国
引用
ジャーナル: Structure / 年: 2022 タイトル: Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium. 著者: Tofayel Ahmed / Collin R Nisler / Edwin C Fluck / Sanket Walujkar / Marcos Sotomayor / Vera Y Moiseenkova-Bell / 要旨: Transient receptor potential (TRP) channels emerged in fungi as mechanosensitive osmoregulators. The Saccharomyces cerevisiae vacuolar TRP yeast 1 (TRPY1) is the most studied TRP channel from fungi, ...Transient receptor potential (TRP) channels emerged in fungi as mechanosensitive osmoregulators. The Saccharomyces cerevisiae vacuolar TRP yeast 1 (TRPY1) is the most studied TRP channel from fungi, but the structure and details of channel modulation remain elusive. Here, we describe the full-length cryoelectron microscopy structure of TRPY1 at 3.1 Å resolution in a closed state. The structure, despite containing an evolutionarily conserved and archetypical transmembrane domain, reveals distinctive structural folds for the cytosolic N and C termini, compared with other eukaryotic TRP channels. We identify an inhibitory phosphatidylinositol 3-phosphate (PI(3)P) lipid-binding site, along with two Ca-binding sites: a cytosolic site, implicated in channel activation and a vacuolar lumen site, implicated in inhibition. These findings, together with data from microsecond-long molecular dynamics simulations and a model of a TRPY1 open state, provide insights into the basis of TRPY1 channel modulation by lipids and Ca, and the molecular evolution of TRP channels.