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J. Biol. Chem., Vol. 283, Issue 7, 3997-4003, February 15, 2008

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Molecular Architecture of Botulinum Neurotoxin E Revealed by Single Particle Electron Microscopy^*

Audrey Fischer, Consuelo Garcia-Rodriguez, Isin Geren, Jianlong Lou, James D. Marks, Terunaga Nakagawa^¶12, and Mauricio Montal¹³

From the Section of Neurobiology, Division of Biological Sciences, and the ^¶Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093-0366 and the Departments of Anesthesia and Pharmaceutical Chemistry, University of California, San Francisco, California 94143

Clostridial botulinum neurotoxin (BoNT) causes a neuroparalytic condition recognized as botulism by arresting synaptic vesicle exocytosis. Although the crystal structures of full-length BoNT/A and BoNT/B holotoxins are known, the molecular architecture of the five other serotypes remains elusive. Here, we present the structures of BoNT/A and BoNT/E using single particle electron microscopy. Labeling of the particles with three different monoclonal antibodies raised against BoNT/E revealed the positions of their epitopes in the electron microscopy structure, thereby identifying the three hallmark domains of BoNT (protease, translocation, and receptor binding). Correspondingly, these antibodies selectively inhibit BoNT translocation activity as detected using a single molecule assay. The global structure of BoNT/E is strikingly different from that of BoNT/A despite strong sequence similarity. We postulate that the unique architecture of functionally conserved modules underlies the distinguishing attributes of BoNT/E and contributes to differences with BoNT/A.

Received for publication, September 21, 2007 , and in revised form, November 6, 2007.

^* This work was supported by the Pacific Southwest Regional Center of Excellence (National Institutes of Health (NIH) Grant AI065359 to M. M.), NIAID/NIH U01 AI056493 (to J. D. M.), and Defense Threat Reduction Agency Contract HDTRA1-07-C-0030 (to J. D. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally as senior authors.

² To whom correspondence may be addressed: 9500 Gilman Dr., La Jolla, CA 92093. Fax: 858-534-7042; E-mail: nakagawa{at}ucsd.edu. ³ To whom correspondence may be addressed. Fax: 858-822-3763; E-mail: mmontal{at}ucsd.edu.

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