title: Processing of Plasmodium falciparum Merozoite Surface Protein MSP1 Activates a Spectrin-Binding Function Enabling Parasite Egress from RBCs.
abstract: The malaria parasite Plasmodium falciparum replicates within erythrocytes, producing progeny merozoites that are released from infected cells via a poorly understood process called egress. The most abundant merozoite surface protein, MSP1, is synthesized as a large precursor that undergoes proteolytic maturation by the parasite protease SUB1 just prior to egress. The function of MSP1 and its processing are unknown. Here we show that SUB1-mediated processing of MSP1 is important for parasite viability. Processing modifies the secondary structure of MSP1 and activates its capacity to bind spectrin, a molecular scaffold protein that is the major component of the host erythrocyte cytoskeleton. Parasites expressing an inefficiently processed MSP1 mutant show delayed egress, and merozoites lacking surface-bound MSP1 display a severe egress defect. Our results indicate that interactions between SUB1-processed merozoite surface MSP1 and the spectrin network of the erythrocyte cytoskeleton facilitate host erythrocyte rupture to enable parasite egress.
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK.
authors.forename: Sujaan
authors.initials: S
authors.lastname: Das
authors.affiliation: Department für Infektiologie, Parasitologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hertrich
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.
authors.forename: Abigail J
authors.initials: AJ
authors.lastname: Perrin
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK.
authors.forename: Chrislaine
authors.initials: C
authors.lastname: Withers-Martinez
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Collins
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Jones
authors.affiliation: Department of Crystallography, Birkbeck College, London, WC1E 7HX, UK.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Watermeyer
authors.affiliation: Department für Infektiologie, Parasitologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Elmar T
authors.initials: ET
authors.lastname: Fobes
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.affiliation: Department of Crystallography, Birkbeck College, London, WC1E 7HX, UK.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Saibil
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK.
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Wright
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK.
authors.forename: Moritz
authors.initials: M
authors.lastname: Treeck
authors.affiliation: Department für Infektiologie, Parasitologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Epp
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, Mill Hill, London, NW7 1AA, UK; Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK. Electronic address: mike.blackman@crick.ac.uk.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
mesh_terms: D004912:Erythrocytes / Q000469:parasitology*; D054884:Host-Pathogen Interactions; D006801:Humans; D020066:Merozoite Surface Protein 1 / Q000737:chemistry / Q000378:metabolism*; D052940:Merozoites / Q000201:enzymology / Q000502:physiology*; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000201:enzymology / Q000502:physiology*; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D015800:Protozoan Proteins / Q000378:metabolism*; D013049:Spectrin / Q000378:metabolism*; D013381:Subtilisins / Q000378:metabolism*
chemical_list: D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; D013049:Spectrin; C443133:SUB1 protein, Toxoplasma gondii; D013381:Subtilisins