title: Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin.
abstract: Venom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, and investigate the interactions of DkTx with the channel and membranes. We find that DkTx binds to the outer edge of the external pore of TRPV1 in a counterclockwise configuration, using a limited protein-protein interface and inserting hydrophobic residues into the bilayer. We also show that DkTx partitions naturally into membranes, with the two lobes exhibiting opposing energetics for membrane partitioning and channel activation. Finally, we find that the toxin disrupts a cluster of hydrophobic residues behind the selectivity filter that are critical for channel activation. Collectively, our findings reveal a novel mode of toxin-channel recognition that has important implications for the mechanism of thermosensation.
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.|Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Chanhyung
authors.initials: C
authors.lastname: Bae
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Claudio
authors.identifier: http://orcid.org/0000-0002-3017-5085
authors.initials: C
authors.lastname: Anselmi
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.|Indian Institute of Science Education and Research, Pune, Pune, India.
authors.forename: Jeet
authors.initials: J
authors.lastname: Kalia
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Andres
authors.initials: A
authors.lastname: Jara-Oseguera
authors.affiliation: Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, United States.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Schwieters
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Krepkiy
authors.affiliation: Department of Chemistry, Chonnam National University, Gwanju, Republic of Korea.
authors.forename: Chul
authors.initials: C
authors.lastname: Won Lee
authors.affiliation: Protein Structure Research Group, Korea Basic Science Institute, Ochang, Republic of Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, United States.
authors.forename: José D
authors.identifier: http://orcid.org/0000-0001-7224-7676
authors.initials: JD
authors.lastname: Faraldo-Gómez
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Kenton J
authors.identifier: http://orcid.org/0000-0003-3419-0765
authors.initials: KJ
authors.lastname: Swartz
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D011485:Protein Binding; D013111:Spider Venoms / Q000737:chemistry* / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D013111:Spider Venoms; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat
keywords: biophysics; capsaicin; membrane channel; membrane structure; protein-protein interactions in membranes; rat; structural biology; thermosensing