A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain

Christopher J. Bohlen; Avi Priel; Sharleen Zhou; David King; Jan Siemens; David Julius

doi:10.1016/j.cell.2010.03.052

A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain

Christopher J. Bohlen, Avi Priel, Sharleen Zhou, David King, Jan Siemens^*, David Julius

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

258 Scopus citations

Abstract

Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and have thus served as invaluable tools for probing channel structure and function. Here, we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high-avidity interaction derives from a unique tandem repeat structure of the toxin that endows it with an antibody-like bivalency. The " double-knot" toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP channels during activation.

Original language	American English
Pages (from-to)	834-845
Number of pages	12
Journal	Cell
Volume	141
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2010.03.052
State	Published - May 2010
Externally published	Yes

Bibliographical note

Funding Information:
We thank Ben Myers for cloning the frog TRPV1 cDNA and making it available for this study, and Roger Nicoll, Alex Chesler, Julio Cordero, Erhu Cao, and other members of our lab for helpful criticism and reading of the manuscript. We also thank the University of California, San Francisco, Mass Spectrometry Resource for instrumentation and technical assistance, supported by the National Institutes of Health (NIH) National Center for Research Resources. This work was supported by a NIH/National Institute of Neurological Disorders and Stroke (NINDS) Ruth Kirschstein predoctoral fellowship (C.B.), postdoctoral fellowships from the Damon Runyon Cancer Research Foundation (A.P.) and the International Human Frontier Science Program Organization (J.S.), and grants from the NIH/NINDS (D.J.).

Keywords

Molneuro
Proteins
Signaling

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10.1016/j.cell.2010.03.052

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abstract = "Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and have thus served as invaluable tools for probing channel structure and function. Here, we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high-avidity interaction derives from a unique tandem repeat structure of the toxin that endows it with an antibody-like bivalency. The {"} double-knot{"} toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP channels during activation.",

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note = "Funding Information: We thank Ben Myers for cloning the frog TRPV1 cDNA and making it available for this study, and Roger Nicoll, Alex Chesler, Julio Cordero, Erhu Cao, and other members of our lab for helpful criticism and reading of the manuscript. We also thank the University of California, San Francisco, Mass Spectrometry Resource for instrumentation and technical assistance, supported by the National Institutes of Health (NIH) National Center for Research Resources. This work was supported by a NIH/National Institute of Neurological Disorders and Stroke (NINDS) Ruth Kirschstein predoctoral fellowship (C.B.), postdoctoral fellowships from the Damon Runyon Cancer Research Foundation (A.P.) and the International Human Frontier Science Program Organization (J.S.), and grants from the NIH/NINDS (D.J.). ",

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AU - King, David

AU - Siemens, Jan

AU - Julius, David

N1 - Funding Information: We thank Ben Myers for cloning the frog TRPV1 cDNA and making it available for this study, and Roger Nicoll, Alex Chesler, Julio Cordero, Erhu Cao, and other members of our lab for helpful criticism and reading of the manuscript. We also thank the University of California, San Francisco, Mass Spectrometry Resource for instrumentation and technical assistance, supported by the National Institutes of Health (NIH) National Center for Research Resources. This work was supported by a NIH/National Institute of Neurological Disorders and Stroke (NINDS) Ruth Kirschstein predoctoral fellowship (C.B.), postdoctoral fellowships from the Damon Runyon Cancer Research Foundation (A.P.) and the International Human Frontier Science Program Organization (J.S.), and grants from the NIH/NINDS (D.J.).

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AB - Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and have thus served as invaluable tools for probing channel structure and function. Here, we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high-avidity interaction derives from a unique tandem repeat structure of the toxin that endows it with an antibody-like bivalency. The " double-knot" toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP channels during activation.

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A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain

Abstract

Bibliographical note

Keywords

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