10779/crick.11842308.v1
Sarah J Tarr
Sarah J
Tarr
Chrislaine Withers-Martinez
Chrislaine
Withers-Martinez
Helen R Flynn
Helen R
Flynn
Ambrosius P Snijders
Ambrosius P
Snijders
Laura Masino
Laura
Masino
Konstantinos Koussis
Konstantinos
Koussis
David J Conway
David J
Conway
Michael J Blackman
Michael J
Blackman
A malaria parasite subtilisin propeptide-like protein is a potent inhibitor of the egress protease SUB1.
The Francis Crick Institute
2020
Plasmodium falciparum
Propeptide
parasitophorous vacuole
subtilase
propeptide
Blackman FC001043
PRT
SB
06 Biological Sciences
11 Medical and Health Sciences
03 Chemical Sciences
Biochemistry & Molecular Biology
2020-02-12 14:56:51
Journal contribution
https://crick.figshare.com/articles/journal_contribution/A_malaria_parasite_subtilisin_propeptide-like_protein_is_a_potent_inhibitor_of_the_egress_protease_SUB1_/11842308
Subtilisin-like serine peptidases (subtilases) play important roles in the life cycle of many organisms, including the protozoan parasites that are the causative agent of malaria, Plasmodium spp. As with other peptidases, subtilase proteolytic activity has to be tightly regulated in order to prevent potentially deleterious uncontrolled protein degradation. Maturation of most subtilases requires the presence of an N-terminal propeptide that facilitates folding of the catalytic domain. Following its proteolytic cleavage, the propeptide acts as a transient, tightly-bound inhibitor until its eventual complete removal to generate active protease. Here we report the identification of a stand-alone malaria parasite propeptide-like protein, called SUB1-ProM, encoded by a conserved gene that lies in a highly syntenic locus adjacent to three of the four subtilisin-like genes in the Plasmodium genome. Template-based modelling and ab initio structure prediction showed that the SUB1-ProM core structure is most similar to the x-ray crystal structure of the propeptide of SUB1, an essential parasite subtilase that is discharged into the parasitophorous vacuole (PV) to trigger parasite release (egress) from infected host cells. Recombinant Plasmodium falciparum SUB1-ProM was found to be a fast-binding, potent inhibitor of P. falciparum SUB1, but not of the only other essential blood-stage parasite subtilase, SUB2, or of other proteases examined. Mass-spectrometry and immunofluorescence showed that SUB1-ProM is expressed in the PV of blood stage P. falciparum, where it may act as an endogenous inhibitor to regulate SUB1 activity in the parasite.