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Science 12 August 2005:
Vol. 309. no. 5737, pp. 1093 - 1096
DOI: 10.1126/science.1113398
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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. Hol2,3{dagger}

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 GS{alpha}, 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.

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

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