A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

David Giganti, Anthony Bouillon, Lina Tawk, Fabienne Robert, Mariano Martinez, Elodie Crublet, Patrick Weber, Christine Girard-Blanc, Stéphane Petres, Ahmed Haouz, Jean-François Hernandez, Odile Mercereau-Puijalon, Pedro M. Alzari and Jean-Christophe Barale ()
Additional contact information
David Giganti: Institut Pasteur, Unité de Microbiologie Structurale
Anthony Bouillon: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites
Lina Tawk: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites
Fabienne Robert: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites
Mariano Martinez: Institut Pasteur, Unité de Microbiologie Structurale
Elodie Crublet: Institut Pasteur, Proteopole & CNRS UMR 3528
Patrick Weber: Institut Pasteur, Proteopole & CNRS UMR 3528
Christine Girard-Blanc: Institut Pasteur, Proteopole & CNRS UMR 3528
Stéphane Petres: Institut Pasteur, Proteopole & CNRS UMR 3528
Ahmed Haouz: Institut Pasteur, Proteopole & CNRS UMR 3528
Jean-François Hernandez: Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, UMR5247, CNRS, Universités Montpellier 1 & 2, 15 avenue Charles Flahault
Odile Mercereau-Puijalon: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites
Pedro M. Alzari: Institut Pasteur, Unité de Microbiologie Structurale
Jean-Christophe Barale: Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract The Plasmodium subtilase SUB1 plays a pivotal role during the egress of malaria parasites from host hepatocytes and erythrocytes. Here we report the crystal structure of full-length SUB1 from the human-infecting parasite Plasmodium vivax, revealing a bacterial-like catalytic domain in complex with a Plasmodium-specific prodomain. The latter displays a novel architecture with an amino-terminal insertion that functions as a ‘belt’, embracing the catalytic domain to further stabilize the quaternary structure of the pre-protease, and undergoes calcium-dependent autoprocessing during subsequent activation. Although dispensable for recombinant enzymatic activity, the SUB1 ‘belt’ could not be deleted in Plasmodium berghei, suggesting an essential role of this domain for parasite development in vivo. The SUB1 structure not only provides a valuable platform to develop new anti-malarial candidates against this promising drug target, but also defines the Plasmodium-specific ‘belt’ domain as a key calcium-dependent regulator of SUB1 during parasite egress from host cells.

Date: 2014
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DOI: 10.1038/ncomms5833

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