PXD024084 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor |
Description | 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. |
HostingRepository | PRIDE |
AnnounceDate | 2021-03-16 |
AnnouncementXML | Submission_2021-03-16_06:42:51.840.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Steven Howell |
SpeciesList | scientific name: Plasmodium falciparum 3D7; NCBI TaxID: 36329; |
ModificationList | monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2021-02-09 07:15:59 | ID requested | |
⏵ 1 | 2021-03-16 06:42:52 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Malaria, protease, SUB1, SERA6, LC-MSMS |
Contact List
Mike Blackman |
contact affiliation | Senior Group Leader Malaria Biochemistry Laboratory Francis Crick Institute London NW1 1AT |
contact email | Mike.Blackman@crick.ac.uk |
lab head | |
Steven Howell |
contact affiliation | Francis Crick Institute |
contact email | steven.howell@crick.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
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[ - ]
- PRIDE
- PXD024084
- Label: PRIDE project
- Name: Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor