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The malaria parasite egress protease SUB1 is activated through precise, plasmepsin X-mediated cleavage of the SUB1 prodomain.
- Source :
-
Biochimica et biophysica acta. General subjects [Biochim Biophys Acta Gen Subj] 2024 Sep; Vol. 1868 (9), pp. 130665. Date of Electronic Publication: 2024 Jul 03. - Publication Year :
- 2024
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Abstract
- Background: The malaria parasite Plasmodium falciparum replicates within red blood cells, then ruptures the cell in a process called egress in order to continue its life cycle. Egress is regulated by a proteolytic cascade involving an essential parasite subtilisin-like serine protease called SUB1. Maturation of SUB1 initiates in the parasite endoplasmic reticulum with autocatalytic cleavage of an N-terminal prodomain (p31), which initially remains non-covalently bound to the catalytic domain, p54. Further trafficking of the p31-p54 complex results in formation of a terminal p47 form of the SUB1 catalytic domain. Recent work has implicated a parasite aspartic protease, plasmepsin X (PMX), in maturation of the SUB1 p31-p54 complex through controlled cleavage of the prodomain p31.<br />Methods: Here we use biochemical and enzymatic analysis to examine the activation of SUB1 by PMX.<br />Results: We show that both p31 and p31-p54 are largely dimeric under the relatively acidic conditions to which they are likely exposed to PMX in the parasite. We confirm the sites within p31 that are cleaved by PMX and determine the order of cleavage. We find that cleavage by PMX results in rapid loss of the capacity of p31 to act as an inhibitor of SUB1 catalytic activity and we directly demonstrate that exposure to PMX of recombinant p31-p54 complex activates SUB1 activity.<br />Conclusions: Our results confirm that precise, PMX-mediated cleavage of the SUB1 prodomain activates SUB1 enzyme activity.<br />General Significance: Our findings elucidate the role of PMX in activation of SUB1, a key effector of malaria parasite egress.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Proteolysis
Humans
Subtilisins metabolism
Catalytic Domain
Protein Domains
Malaria, Falciparum parasitology
Malaria, Falciparum metabolism
Erythrocytes parasitology
Erythrocytes metabolism
Plasmodium falciparum enzymology
Plasmodium falciparum metabolism
Aspartic Acid Endopeptidases metabolism
Aspartic Acid Endopeptidases genetics
Protozoan Proteins metabolism
Protozoan Proteins genetics
Protozoan Proteins chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1872-8006
- Volume :
- 1868
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. General subjects
- Publication Type :
- Academic Journal
- Accession number :
- 38969256
- Full Text :
- https://doi.org/10.1016/j.bbagen.2024.130665