Reports

Structural Basis for the Activation of Cholera Toxin by Human ARF6-GTP

Claire J. O'Neal,^1* Michael G. Jobling,^4* Randall K. Holmes,⁴ Wim G. J. Hol^2,3

The Vibrio cholerae bacterium causes devastating diarrhea when it infects the human intestine. The key event is adenosine diphosphate (ADP)–ribosylation of the human signaling protein G_S, catalyzed by the cholera toxin A1 subunit (CTA1). This reaction is allosterically activated by human ADP-ribosylation factors (ARFs), a family of essential and ubiquitous G proteins. Crystal structures of a CTA1:ARF6-GTP (guanosine triphosphate) complex reveal that binding of the human activator elicits dramatic changes in CTA1 loop regions that allow nicotinamide adenine dinucleotide (NAD⁺) to bind to the active site. The extensive toxin:ARF-GTP interface surface mimics ARF-GTP recognition of normal cellular protein partners, which suggests that the toxin has evolved to exploit promiscuous binding properties of ARFs.

¹ Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
² Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
³ Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
⁴ Department of Microbiology, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: wghol{at}u.washington.edu

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PNAS 105, 7399-7404
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P. O. Hassa, S. S. Haenni, M. Elser, and M. O. Hottiger (2006)
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Electrostatic Properties of Protein-Protein Complexes.

P. J. Kundrotas and E. Alexov (2006)
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Dual Specificity of the Interfacial Inhibitor Brefeldin A for Arf Proteins and Sec7 Domains.

J.-C. Zeeh, M. Zeghouf, C. Grauffel, B. Guibert, E. Martin, A. Dejaegere, and J. Cherfils (2006)
J. Biol. Chem. 281, 11805-11814
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The Cholera Toxin A13 Subdomain Is Essential for Interaction with ADP-Ribosylation Factor 6 and Full Toxic Activity but Is Not Required for Translocation from the Endoplasmic Reticulum to the Cytosol.

K. Teter, M. G. Jobling, D. Sentz, and R. K. Holmes (2006)
Infect. Immun. 74, 2259-2267
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