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

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journal contribution
posted on 2021-06-16, 11:06 authored by Michele SY Tan, Konstantinos Koussis, Chrislaine Withers-Martinez, Steven A Howell, James A Thomas, Fiona Hackett, Ellen Knuepfer, Min Shen, Matthew D Hall, Ambrosius P Snijders, Michael J Blackman
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 β-spectrin. Here, we show that the 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 β-spectrin cleavage and RBC rupture. Drug-like inhibitors of SERA6 autoprocessing similarly prevent β-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.


Crick (Grant ID: 10043, Grant title: Blackman FC001043) Crick (Grant ID: 10011, Grant title: STP Proteomics) Wellcome Trust (Grant ID: 106239/Z/14/A, Grant title: WT 106239/Z/14/A) Medical Research Council (Grant ID: MC_PC_17179, Grant title: CiC 2017: Crick Idea to Innovation (i2i))