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The enzymes are synthesized as inactive zymogens (pro\u2010PMs), and the mechanism of their conversion to the active, mature forms has not been clearly elucidated. Our structural investigations of vacuolar pro\u2010PMs with truncated prosegment (pro\u2010tPMs) reveal that the formation of the S\u2010shaped dimer is their innate property. Further structural studies, biochemical analysis, and molecular dynamics simulations indicate that disruption of the Tyr\u2010Asp loop (121p\u20104), coordinated with the movement of the loop L1 (237\u2013247) and helix H2 (101p\u2013113p), is responsible for the extension of the pro\u2010mature 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\u2010tPMs with the unfolded prosegment is accessible for peptide substrate binding; in contrast, the active site is blocked in folded prosegment form of pro\u2010tPMs. Thus, we propose a novel mechanism of auto\u2010activation of vacuolar pro\u2010tPMs that under acidic conditions can form a catalytically competent active site. One monomer cleaves the prosegment of the other one through a trans\u2010activation 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\u2010tPMs to their mature form.<\/jats:p><\/jats:sec><jats:sec><jats:title>Database<\/jats:title><jats:p>Atomic coordinates and structure factors have been submitted in the Protein Data Bank (PDB) under the PDB IDs <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/6KUB\">6KUB<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/6KUC\">6KUC<\/jats:ext-link>, and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/6KUD\">6KUD<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.15363","type":"journal-article","created":{"date-parts":[[2020,5,9]],"date-time":"2020-05-09T08:55:55Z","timestamp":1589014555000},"page":"678-698","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Activation mechanism of plasmepsins, pepsin\u2010like aspartic proteases from <i>Plasmodium,<\/i> follows a unique trans\u2010activation pathway"],"prefix":"10.1111","volume":"288","author":[{"given":"Ishan","family":"Rathore","sequence":"first","affiliation":[{"name":"Department of Biosciences and Bioengineering Indian Institute of Technology Bombay Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Bioengineering Indian Institute of Technology Bombay Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandan","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Chemistry Indian Institute of Technology Bombay Mumbai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huogen","family":"Xiao","sequence":"additional","affiliation":[{"name":"Summerland Research and Development Centre Agriculture and 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