{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:18:40Z","timestamp":1787026720770,"version":"build-2736575974"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>\n                    Mechanisms of leptospirosis pathogenesis remain unclear despite the identification of a number of potential leptospiral virulence factors. We recently demonstrated potential mechanisms by which the virulence-modifying (VM) proteins\u2014defined as containing a Domain of Unknown function (DUF1561), encoded by the PF07598 gene family\u2014found only in group 1 pathogenic\n                    <jats:italic>Leptospira<\/jats:italic>\n                    \u2014might mediate the clinical pathogenesis of leptospirosis. VM proteins belongs to classical AB toxin paradigm though have a unique AB domain architecture, unlike other AB toxins such as diphtheria toxin, pertussis toxin, shiga toxin, or ricin toxin which are typically encoded by two or more genes and self-assembled into a multi-domain holotoxin. Leptospiral VM proteins are secreted R-type lectin domain-containing exotoxins with discrete N-terminal ricin B-like domains involved in host cell surface binding, and a C-terminal DNase\/toxin domain. Here we use the artificial intelligence-based AlphaFold algorithm and other computational tools to predict and elaborate on details of the VM protein structure-function relationship. Comparative AlphaFold and CD-spectroscopy defined the consistent secondary structure (Helix and \u00df-sheet) content, and the stability of the functional domains were further supported by molecular dynamics simulation. VM proteins comprises distinctive lectic family (QxW)\n                    <jats:sub>3<\/jats:sub>\n                    motifs, the\n                    <jats:italic>Mycoplasma<\/jats:italic>\n                    CARDS toxin (D3 domain, aromatic patches), C-terminal similarity with mammalian DNase I.\n                    <jats:italic>In-silico<\/jats:italic>\n                    study proposed that Gln412, Gln523, His533, Thr59 are the high binding energy or ligand binding residues plausibly anticipates in the functional activities. Divalent cation (Mg\n                    <jats:sup>+2<\/jats:sup>\n                    -Gln412) and phosphate ion (PO\n                    <jats:sub>4<\/jats:sub>\n                    ]\n                    <jats:sup>\u22123<\/jats:sup>\n                    -Arg615) interaction further supports the functional activities driven by C-terminal domain. Computation-driven structure-function studies of VM proteins will guide experimentation towards mechanistic understandings of leptospirosis pathogenesis, which underlie development of new therapeutic and preventive measures for this devastating disease.\n                  <\/jats:p>","DOI":"10.3389\/fmolb.2022.1092197","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T06:35:01Z","timestamp":1674455701000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["In silico prediction of molecular mechanisms of toxicity mediated by the leptospiral PF07598 gene family-encoded virulence-modifying proteins"],"prefix":"10.3389","volume":"9","author":[{"given":"Reetika","family":"Chaurasia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Vinetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e36466","DOI":"10.1371\/journal.pone.0036466","article-title":"A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy","volume":"7","author":"Aagaard","year":"2012","journal-title":"PLoS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.vetmic.2009.03.012","article-title":"Leptospira and leptospirosis","volume":"140","author":"Adler","year":"2010","journal-title":"Vet. 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