title: Role of plasmepsin V in export of diverse protein families from the Plasmodium falciparum exportome.
abstract: Plasmodium falciparum exports several hundred effector proteins that remodel the host erythrocyte and enable parasites to acquire nutrients, sequester in the circulation and evade immune responses. The majority of exported proteins contain the Plasmodium export element (PEXEL; RxLxE/Q/D) in their N-terminus, which is proteolytically cleaved in the parasite endoplasmic reticulum by Plasmepsin V, and is necessary for export. Several exported proteins lack a PEXEL or contain noncanonical motifs. Here, we assessed whether Plasmepsin V could process the N-termini of diverse protein families in P. falciparum. We show that Plasmepsin V cleaves N-terminal sequences from RIFIN, STEVOR and RESA multigene families, the latter of which contain a relaxed PEXEL (RxLxxE). However, Plasmepsin V does not cleave the N-terminal sequence of the major exported virulence factor erythrocyte membrane protein 1 (PfEMP1) or the PEXEL-negative exported proteins SBP-1 or REX-2. We probed the substrate specificity of Plasmepsin V and determined that lysine at the PEXEL P3 position, which is present in PfEMP1 and other putatively exported proteins, blocks Plasmepsin V activity. Furthermore, isoleucine at position P1 also blocked Plasmepsin V activity. The specificity of Plasmepsin V is therefore exquisitely confined and we have used this novel information to redefine the predicted P. falciparum PEXEL exportome.
authors: Division of Infection and Immunity, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. boddey@wehi.edu.au
authors: Justin A
authors: JA
authors: Boddey
authors: Teresa G
authors: TG
authors: Carvalho
authors: Anthony N
authors: AN
authors: Hodder
authors: Tobias J
authors: TJ
authors: Sargeant
authors: Brad E
authors: BE
authors: Sleebs
authors: Danushka
authors: D
authors: Marapana
authors: Sash
authors: S
authors: Lopaticki
authors: Thomas
authors: T
authors: Nebl
authors: Alan F
authors: AF
authors: Cowman
mesh_terms: D020816:Amino Acid Motifs; D000953:Antigens, Protozoan / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000469:parasitology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000378:metabolism*; D012984:Software; D013347:Subcellular Fractions; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D002352:Carrier Proteins; D008565:Membrane Proteins; C417763:Pfsbp1 protein, Plasmodium falciparum; D015800:Protozoan Proteins; C534665:RIFIN protein, Plasmodium falciparum; C474556:STEVOR antigen, Plasmodium falciparum; D037521:Virulence Factors; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin