Serial femtosecond crystallography on in vivo-grown crystals drives elucidation of mosquitocidal Cyt1Aa bioactivation cascade

Guillaume Tetreau, Anne-Sophie Banneville, Elena A. Andreeva, Aaron S. Brewster, Mark S. Hunter, Raymond G. Sierra, Jean-Marie Teulon, Iris D. Young, Niamh Burke, Tilman A. Grünewald, Joël Beaudouin, Irina Snigireva, Maria Teresa Fernandez-Luna, Alister Burt, Hyun-Woo Park, Luca Signor, Jayesh A. Bafna, Rabia Sadir, Daphna Fenel, Elisabetta Boeri-Erba, Maria Bacia, Ninon Zala, Frédéric Laporte, Laurence Després, Martin Weik, Sébastien Boutet, Martin Rosenthal, Nicolas Coquelle, Manfred Burghammer, Duilio Cascio, Michael R. Sawaya, Mathias Winterhalter, Enrico Gratton, Irina Gutsche, Brian Federici, Jean-Luc Pellequer, Nicholas K. Sauter and Jacques-Philippe Colletier ()
Additional contact information
Guillaume Tetreau: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Anne-Sophie Banneville: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Elena A. Andreeva: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Aaron S. Brewster: Lawrence Berkeley National Laboratory
Mark S. Hunter: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Raymond G. Sierra: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Jean-Marie Teulon: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Iris D. Young: Lawrence Berkeley National Laboratory
Niamh Burke: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Tilman A. Grünewald: European Synchrotron Radiation Facility (ESRF), BP 220
Joël Beaudouin: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Irina Snigireva: European Synchrotron Radiation Facility (ESRF), BP 220
Maria Teresa Fernandez-Luna: University of California
Alister Burt: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Hyun-Woo Park: University of California
Luca Signor: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Jayesh A. Bafna: Jacobs University
Rabia Sadir: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Daphna Fenel: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Elisabetta Boeri-Erba: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Maria Bacia: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Ninon Zala: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Frédéric Laporte: Univ. Grenoble Alpes, CNRS, LECA
Laurence Després: Univ. Grenoble Alpes, CNRS, LECA
Martin Weik: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Sébastien Boutet: Linac Coherent Light Source, SLAC National Accelerator Laboratory
Martin Rosenthal: European Synchrotron Radiation Facility (ESRF), BP 220
Nicolas Coquelle: Large-Scale Structures Group, Institut Laue-Langevin
Manfred Burghammer: European Synchrotron Radiation Facility (ESRF), BP 220
Duilio Cascio: University of California
Michael R. Sawaya: University of California
Mathias Winterhalter: Univ. Grenoble Alpes, CNRS, LECA
Enrico Gratton: The Henry Samueli School of Engineering, University of California
Irina Gutsche: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Brian Federici: University of California
Jean-Luc Pellequer: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale
Nicholas K. Sauter: Lawrence Berkeley National Laboratory
Jacques-Philippe Colletier: Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Cyt1Aa is the one of four crystalline protoxins produced by mosquitocidal bacterium Bacillus thuringiensis israelensis (Bti) that has been shown to delay the evolution of insect resistance in the field. Limiting our understanding of Bti efficacy and the path to improved toxicity and spectrum has been ignorance of how Cyt1Aa crystallizes in vivo and of its mechanism of toxicity. Here, we use serial femtosecond crystallography to determine the Cyt1Aa protoxin structure from sub-micron-sized crystals produced in Bti. Structures determined under various pH/redox conditions illuminate the role played by previously uncharacterized disulfide-bridge and domain-swapped interfaces from crystal formation in Bti to dissolution in the larval mosquito midgut. Biochemical, toxicological and biophysical methods enable the deconvolution of key steps in the Cyt1Aa bioactivation cascade. We additionally show that the size, shape, production yield, pH sensitivity and toxicity of Cyt1Aa crystals grown in Bti can be controlled by single atom substitution.

Date: 2020
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DOI: 10.1038/s41467-020-14894-w

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