Proteomics

Dataset Information

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Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor


ABSTRACT: Malaria parasite egress from host erythrocytes (RBCs) is regulated by discharge of a parasite serine protease called SUB1 into the parasitophorous vacuole (PV). There, SUB1 activates a PV-resident cysteine protease called SERA6, enabling host RBC rupture through SERA6-mediated degradation of the RBC cytoskeleton protein beta-spectrin. Here we show that activation of Plasmodium falciparum SERA6 involves a second, autocatalytic step that is triggered by SUB1 cleavage. Unexpectedly, autoproteolytic maturation of SERA6 requires interaction in multimolecular complexes with a distinct PV-located protein cofactor, MSA180, that is itself a SUB1 substrate. Genetic ablation of MSA180 mimics SERA6 disruption, producing a fatal block in beta-spectrin cleavage and RBC rupture. Drug-like inhibitors of SERA6 autoprocessing similarly prevent beta-spectrin cleavage and egress in both P. falciparum and the emerging zoonotic pathogen P. knowlesi. Our results elucidate the egress pathway and identify SERA6 as a target for a new class of antimalarial drugs designed to prevent disease progression.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Plasmodium Falciparum (isolate 3d7)

DISEASE(S): Malaria

SUBMITTER: Steven Howell  

LAB HEAD: Mike Blackman

PROVIDER: PXD024084 | Pride | 2021-03-16

REPOSITORIES: Pride

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