PXD024084

PXD024084 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-09 07:15:59	ID requested
⏵ 1	2021-03-16 06:42:52	announced

Dataset with its publication pending

submitter keyword: Malaria, protease, SUB1, SERA6, LC-MSMS

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

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PRIDE project URI

• PRIDE
  1. PXD024084
     1. Label: PRIDE project
     2. Name: Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor