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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,20]]},"abstract":"<jats:p>\n                    The complexity of snake venom composition reflects adaptation to the diversity of prey and may be driven at times by a coevolutionary arms race between snakes and venom-resistant prey. However, many snakes are also resistant to their own venom due to serum-borne inhibitors of venom toxins, which raises the question of how snake autoinhibitors maintain their efficacy as venom proteins evolve. To investigate this potential three-way arms race among venom, prey, and autoinhibitors, we have identified and traced the evolutionary origin of serum inhibitors of snake venom metalloproteinases (SVMPs) in the Western Diamondback rattlesnake\n                    <jats:italic>Crotalus atrox<\/jats:italic>\n                    which possesses the largest known battery of SVMP genes among crotalids examined. We found that\n                    <jats:italic>C.\u00a0atrox<\/jats:italic>\n                    expresses five members of a Fetuin A-related metalloproteinase inhibitor family but that one family member, FETUA-3, is the major SVMP inhibitor that binds to approximately 20 different\n                    <jats:italic>C.\u00a0atrox<\/jats:italic>\n                    SVMPs and inhibits activities of all three SVMP classes. We show that the\n                    <jats:italic>fetua-3<\/jats:italic>\n                    gene arose deep within crotalid evolution before the origin of New World species but, surprisingly,\n                    <jats:italic>fetua-3<\/jats:italic>\n                    belongs to a different paralog group than previously identified SVMP inhibitors in Asian and South American crotalids. Conversely, the\n                    <jats:italic>C.\u00a0atrox<\/jats:italic>\n                    FETUA-2 ortholog of previously characterized crotalid SVMP inhibitors shows limited activity against\n                    <jats:italic>C.\u00a0atrox<\/jats:italic>\n                    SVMPs. These results reveal that there has been a functional evolutionary shift in the major SVMP inhibitor in the\n                    <jats:italic>C.\u00a0atrox<\/jats:italic>\n                    lineage as the SVMP family expanded and diversified in the\n                    <jats:italic>Crotalus<\/jats:italic>\n                    lineage. This broad-spectrum inhibitor may be of potential therapeutic interest.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2214880119","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T10:38:30Z","timestamp":1672310310000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":14,"title":["A novel broad spectrum venom metalloproteinase autoinhibitor in the rattlesnake\n                    <i>Crotalus atrox<\/i>\n                    evolved via a shift in paralog function"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4251-4531","authenticated-orcid":false,"given":"Fiona P.","family":"Ukken","sequence":"first","affiliation":[{"name":"HHMI, University of Maryland \u2013 College Park, College Park, MD 20742"},{"name":"Department of Biology, University of Maryland \u2013 College Park, College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-6567","authenticated-orcid":false,"given":"Noah L.","family":"Dowell","sequence":"additional","affiliation":[{"name":"HHMI, University of Maryland \u2013 College Park, College Park, MD 20742"},{"name":"Department of Biology, University of Maryland \u2013 College Park, College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamta","family":"Hajra","sequence":"additional","affiliation":[{"name":"HHMI, University of Maryland \u2013 College Park, College Park, MD 20742"},{"name":"Department of Biology, University of Maryland \u2013 College Park, College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7839-5458","authenticated-orcid":false,"given":"Sean B.","family":"Carroll","sequence":"additional","affiliation":[{"name":"HHMI, University of Maryland \u2013 College Park, College Park, MD 20742"},{"name":"Department of Biology, University of Maryland \u2013 College Park, College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1964.tb01674.x"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1558-5646.1980.tb04849.x"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.3228405"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","unstructured":"J. van Thiel Convergent evolution of toxin resistance in animals. 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