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Leukemia inhibitory factor receptor is triggered by the IL\u20106 family proteins: leukemia inhibitory factor (LIF), oncostatin\u2010M (OSM), cardiotrophin\u20101 (CT\u20101), ciliary neurotrophic factor (CNTF), and cardiotrophin\u2010like cytokine factor 1 (CLCF1). Besides the conserved binding sites to the receptor, not much is known in terms of the diversity and characteristics of these proteins in different organisms. Herein, we describe the sequence analysis of LIF, OSM, and CT\u20101 from several organisms, and m17, a LIF ortholog found in fishes, regarding its phylogenetics, intrinsic properties, and the impact of conserved residues on structural features. Sequences were identified in seven classes of vertebrates, showing high conservation values in binding site III, but protein\u2010dependent results on binding site II. GRAVY, isoelectric point, and molecular weight parameters were relevant to differentiate classes in each protein and to enable, for the first time and with high fidelity, the prediction of both organism class and protein type just using machine learning approaches. OSM sequences from primates showed an increased BC loop when compared to the remaining mammals, which could influence binding to OSM receptor and tune signaling pathways. Overall, this study highlights the potential of sequence diversity analysis to understand IL\u20106 cytokine family evolution, showing the conservation of function\u2010related motifs and evolution of class and protein\u2010dependent characteristics. Our results could impact future medical treatment of disorders associated with imbalances in these cytokines.<\/jats:p>","DOI":"10.1002\/pro.4469","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T10:49:07Z","timestamp":1665571747000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Uncovering the promiscuous activity of <scp>IL<\/scp>\u20106 proteins: A multi\u2010dimensional analysis of phylogeny, classification and residue conservation"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4098-2083","authenticated-orcid":false,"given":"Andr\u00e9 da","family":"Costa","sequence":"first","affiliation":[{"name":"CBMA \u2010 Centre of Molecular and Environmental Biology, Department of Biology University of Minho  Braga Portugal"},{"name":"IB\u2010S Institute of Science and Innovation for Sustainability University of Minho  Braga 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