title: A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase.
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.
authors.affiliation: 1] Institut Pasteur, Unité de Microbiologie Structurale, Département de Biologie Structurale et Chimie, F-75015 Paris, France [2] CNRS UMR 3528, F-75015 Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Giganti
authors.affiliation: 1] Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France [2] CNRS URA 2581, F-75015 Paris, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bouillon
authors.affiliation: 1] Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France [2] CNRS URA 2581, F-75015 Paris, France.
authors.forename: Lina
authors.initials: L
authors.lastname: Tawk
authors.affiliation: 1] Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France [2] CNRS URA 2581, F-75015 Paris, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Robert
authors.affiliation: 1] Institut Pasteur, Unité de Microbiologie Structurale, Département de Biologie Structurale et Chimie, F-75015 Paris, France [2] CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Mariano
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Institut Pasteur, Proteopole &CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Crublet
authors.affiliation: Institut Pasteur, Proteopole &CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weber
authors.affiliation: Institut Pasteur, Proteopole &CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Girard-Blanc
authors.affiliation: Institut Pasteur, Proteopole &CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Petres
authors.affiliation: Institut Pasteur, Proteopole &CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.affiliation: Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, UMR5247, CNRS, Universités Montpellier 1 &2, 15 avenue Charles Flahault, 34093 Montpellier cedex 5, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hernandez
authors.affiliation: 1] Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France [2] CNRS URA 2581, F-75015 Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: 1] Institut Pasteur, Unité de Microbiologie Structurale, Département de Biologie Structurale et Chimie, F-75015 Paris, France [2] CNRS UMR 3528, F-75015 Paris, France [3] Institut Pasteur, Proteopole &CNRS UMR 3528, F-75015 Paris, France.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Alzari
authors.affiliation: 1] Institut Pasteur, Unité d'Immunologie Moléculaires des Parasites, Département de Parasitologie et de Mycologie, F-75015 Paris, France [2] CNRS URA 2581, F-75015 Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Barale
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000627:therapeutic use; D003461:Crystallography; D006801:Humans; D016780:Malaria, Vivax / Q000188:drug therapy; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010962:Plasmodium berghei; D010966:Plasmodium vivax; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000378:metabolism*; D013381:Subtilisins / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D013381:Subtilisins