{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:42:46Z","timestamp":1767181366924,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011902","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000}}],"reference-count":80,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T00:00:00Z","timestamp":1708041600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["101028908"],"award-info":[{"award-number":["101028908"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    The pathogenic, tropical\n                    <jats:italic>Leishmania<\/jats:italic>\n                    flagellates belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Unfortunately, they are poorly understood from a molecular biology perspective, making development of mechanistically novel and selective drugs difficult. Here, we explore three functionally critical targeting short linear motif systems as well as their receptors in depth, using a combination of structural modeling, evolutionary sequence divergence and deep learning. Secretory signal peptides, endoplasmic reticulum (ER) retention motifs (KDEL motifs), and autophagy signals (motifs interacting with ATG8 family members) are ancient and essential components of cellular life. Although expected to be conserved amongst the kinetoplastids, we observe that all three systems show a varying degree of divergence from their better studied equivalents in animals, plants, or fungi. We not only describe their behaviour, but also build models that allow the prediction of localization and potential functions for several uncharacterized\n                    <jats:italic>Leishmania<\/jats:italic>\n                    proteins. The unusually Ala\/Val-rich secretory signal peptides, endoplasmic reticulum resident proteins ending in Asp-Leu-COOH and atypical ATG8-like proteins are all unique molecular features of kinetoplastid parasites. Several of their critical protein-protein interactions could serve as targets of selective antimicrobial agents against Leishmaniasis due to their systematic divergence from the host.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1011902","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T13:33:19Z","timestamp":1708090399000},"page":"e1011902","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents"],"prefix":"10.1371","volume":"20","author":[{"given":"Andras","family":"Zeke","sequence":"first","affiliation":[]},{"given":"Toby J.","family":"Gibson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2765-3872","authenticated-orcid":true,"given":"Laszlo","family":"Dobson","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2024,2,16]]},"reference":[{"key":"pcbi.1011902.ref001","doi-asserted-by":"crossref","first-page":"D442","DOI":"10.1093\/nar\/gkad1058","article-title":"ELM\u2014the Eukaryotic Linear Motif resource\u20142024 update","volume":"52","author":"M Kumar","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011902.ref002","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12964-015-0120-z","article-title":"Short linear motifs\u2014ex nihilo evolution of protein regulation","volume":"13","author":"NE Davey","year":"2015","journal-title":"Cell Commun Signal"},{"key":"pcbi.1011902.ref003","doi-asserted-by":"crossref","first-page":"1233281","DOI":"10.3389\/fbinf.2023.1233281","article-title":"The origin of eukaryotes and rise in complexity were synchronous with the rise in oxygen","volume":"3","author":"JM Craig","year":"2023","journal-title":"Front Bioinform"},{"key":"pcbi.1011902.ref004","doi-asserted-by":"crossref","first-page":"15386","DOI":"10.1073\/pnas.0403984101","article-title":"The timing of eukaryotic evolution: does a relaxed molecular clock reconcile proteins and fossils","volume":"101","author":"EJP Douzery","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011902.ref005","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S0092-8674(00)80443-2","article-title":"Protein translocation in the three domains of life: variations on a theme","volume":"91","author":"M Pohlschr\u00f6der","year":"1997","journal-title":"Cell"},{"key":"pcbi.1011902.ref006","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/j.1365-2958.2004.04139.x","article-title":"A structural step into the SRP cycle","volume":"53","author":"K Wild","year":"2004","journal-title":"Mol Microbiol"},{"key":"pcbi.1011902.ref007","doi-asserted-by":"crossref","first-page":"7163","DOI":"10.1038\/ncomms8163","article-title":"Signal-sequence induced conformational changes in the signal recognition particle.","volume":"6","author":"T Hainzl","year":"2015","journal-title":"Nat Commun"},{"key":"pcbi.1011902.ref008","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.cell.2011.06.004","article-title":"Stepwise insertion and inversion of a type II signal anchor sequence in the ribosome-Sec61 translocon complex","volume":"146","author":"PK Devaraneni","year":"2011","journal-title":"Cell"},{"key":"pcbi.1011902.ref009","doi-asserted-by":"crossref","first-page":"16903","DOI":"10.1038\/s41598-020-73906-3","article-title":"The KDEL trafficking receptor exploits pH to tune the strength of an unusual short hydrogen bond","volume":"10","author":"Z Wu","year":"2020","journal-title":"Sci Rep"},{"key":"pcbi.1011902.ref010","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1016\/j.febslet.2009.10.053","article-title":"The KDEL receptor: new functions for an old protein","volume":"583","author":"M Capitani","year":"2009","journal-title":"FEBS Lett"},{"key":"pcbi.1011902.ref011","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fpls.2020.00343","article-title":"A Model for ERD2","volume":"11","author":"DG Robinson","year":"2020","journal-title":"Function in Higher Plants. 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