Cell
Volume 141, Issue 5, 28 May 2010, Pages 834-845
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Article
A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain

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Summary

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.

Highlights

► DkTx is a spider toxin that irreversibly activates the capsaicin receptor, TRPV1 ► DkTx's tandem-repeat sequence underlies its bivalent, high-avidity TRPV1 interaction ► DkTx and related toxins bind to residues within the outer pore domain of TRPV1 ► Conformational changes in the outer pore are critical for TRP channel activation

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SIGNALING
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3

These authors contributed equally to this work

4

Present address: Max-Delbrück-Centrum für Molekulare Medizin, Berlin-Buch, Robert-Rössle-Strasse 10, 13125 Berlin, Germany