Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium.

Tofayel Ahmed, Collin R Nisler, Edwin C Fluck, Sanket Walujkar, Marcos Sotomayor, Vera Y Moiseenkova-Bell

Structure (London, England : 1993) 2022 Jan 06

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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 Ca2+-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 Ca2+, and the molecular evolution of TRP channels. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Tofayel Ahmed, Collin R Nisler, Edwin C Fluck, Sanket Walujkar, Marcos Sotomayor, Vera Y Moiseenkova-Bell. Structure of the ancient TRPY1 channel from Saccharomyces cerevisiae reveals mechanisms of modulation by lipids and calcium. Structure (London, England : 1993). 2022 Jan 06;30(1):139-155.e5