title: Hierarchical phosphorylation of apical membrane antigen 1 is required for efficient red blood cell invasion by malaria parasites.
abstract: Central to the pathogenesis of malaria is the proliferation of Plasmodium falciparum parasites within human erythrocytes. Parasites invade erythrocytes via a coordinated sequence of receptor-ligand interactions between the parasite and host cell. One key ligand, Apical Membrane Antigen 1 (AMA1), is a leading blood-stage vaccine and previous work indicates that phosphorylation of its cytoplasmic domain (CPD) is important to its function during invasion. Here we investigate the significance of each of the six available phospho-sites in the CPD. We confirm that the cyclic AMP/protein kinase A (PKA) signalling pathway elicits a phospho-priming step upon serine 610 (S610), which enables subsequent phosphorylation in vitro of a conserved, downstream threonine residue (T613) by glycogen synthase kinase 3 (GSK3). Both phosphorylation steps are required for AMA1 to function efficiently during invasion. This provides the first evidence that the functions of key invasion ligands of the malaria parasite are regulated by sequential phosphorylation steps.
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.|Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Prinz
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.|Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Harvey
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.|Department of Pathology and Molecular Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Louisa
authors.initials: L
authors.lastname: Wilcke
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Ruch
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Engelberg
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Biller
authors.affiliation: Chemical Biology Division, The Walter and Eliza Hall Institute, Melbourne, Victoria 3052, Australia.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lucet
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Erkelenz
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Heincke
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Spielmann
authors.affiliation: Department of Microbiology, Monash University, Victoria 3800, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
authors.affiliation: Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.|Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria 3010, Australia.|Department of Microbiology, Monash University, Victoria 3800, Australia.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria 3004, Australia.|Department of Microbiology, Monash University, Victoria 3800, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.affiliation: Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany.|Department of Pathology and Molecular Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.|Centre for Structural Systems Biology, 22607 Hamburg, Germany.
authors.forename: Tim W
authors.initials: TW
authors.lastname: Gilberger
mesh_terms: D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D000072417:Protein Domains; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems
chemical_list: D000953:Antigens, Protozoan; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases