4.6 Article

Activation mechanism of plasmepsins, pepsin-like aspartic proteases from Plasmodium, follows a unique trans-activation pathway

期刊

FEBS JOURNAL
卷 288, 期 2, 页码 678-698

出版社

WILEY
DOI: 10.1111/febs.15363

关键词

enzyme activation; histo-aspartic protease; plasmepsin I; plasmepsin II; plasmepsin IV

资金

  1. University Grant Commission (UGC)
  2. Department of Biotechnology (DBT), Ministry of Science and Technology, India
  3. Ramalingaswami Re-entry Fellowship (DBT)
  4. IRCC, IIT Bombay
  5. Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
  6. Natural Sciences and Engineering Research Council of Canada

向作者/读者索取更多资源

Plasmodium parasites producing plasmepsins are important drug targets. Structural studies show the S-shaped dimer formation of vacuolar pro-PMs. Disruption of the Tyr-Asp loop leads to extension of the pro-mature region and activation of the enzyme under acidic conditions. The auto-activation mechanism involves cleaving of one prosegment by another to generate mature enzymes.
Plasmodium parasites that cause malaria produce plasmepsins (PMs), pepsin-like aspartic proteases that are important antimalarial drug targets due to their role in host hemoglobin degradation. The enzymes are synthesized as inactive zymogens (pro-PMs), and the mechanism of their conversion to the active, mature forms has not been clearly elucidated. Our structural investigations of vacuolar pro-PMs with truncated prosegment (pro-tPMs) reveal that the formation of the S-shaped dimer is their innate property. Further structural studies, biochemical analysis, and molecular dynamics simulations indicate that disruption of the Tyr-Asp loop (121p-4), coordinated with the movement of the loop L1 (237-247) and helix H2 (101p-113p), is responsible for the extension of the pro-mature region (harboring the cleavage site). Consequently, under acidic pH conditions, these structural changes result in the dissociation of the dimers to monomers and the protonation of the residues in the prosegment prompts its unfolding. Subsequently, we demonstrated that the active site of the monomeric pro-tPMs with the unfolded prosegment is accessible for peptide substrate binding; in contrast, the active site is blocked in folded prosegment form of pro-tPMs. Thus, we propose a novel mechanism of auto-activation of vacuolar pro-tPMs that under acidic conditions can form a catalytically competent active site. One monomer cleaves the prosegment of the other one through a trans-activation process, resulting in formation of mature enzyme. As a result, once a mature enzyme is generated, it leads to the complete conversion of all the inactive pro-tPMs to their mature form. Database Atomic coordinates and structure factors have been submitted in the Protein Data Bank (PDB) under the PDB IDs , , and .

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