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The underlying molecular basis of how the lectin domains of GalNAc-Ts contribute to glycopeptide specificity and catalysis remains unclear. Here we present the first crystal structures of complexes of GalNAc-T2 with glycopeptides that together with enhanced sampling molecular dynamics simulations demonstrate a cooperative mechanism by which the lectin domain enables free acceptor sites binding of glycopeptides into the catalytic domain. Atomic force microscopy and small-angle X-ray scattering experiments further reveal a dynamic conformational landscape of GalNAc-T2 and a prominent role of compact structures that are both required for efficient catalysis. Our model indicates that the activity profile of GalNAc-T2 is dictated by conformational heterogeneity and relies on a flexible linker located between the catalytic and the lectin domains. Our results also shed light on how GalNAc-Ts generate dense decoration of proteins with <jats:italic>O<\/jats:italic>-glycans.<\/jats:p>","DOI":"10.1038\/ncomms7937","type":"journal-article","created":{"date-parts":[[2015,5,5]],"date-time":"2015-05-05T11:23:19Z","timestamp":1430824999000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation"],"prefix":"10.1038","volume":"6","author":[{"given":"Erandi","family":"Lira-Navarrete","sequence":"first","affiliation":[]},{"given":"Matilde","family":"de las Rivas","sequence":"additional","affiliation":[]},{"given":"Ismael","family":"Compa\u00f1\u00f3n","sequence":"additional","affiliation":[]},{"given":"Mar\u00eda Carmen","family":"Pallar\u00e9s","sequence":"additional","affiliation":[]},{"given":"Yun","family":"Kong","sequence":"additional","affiliation":[]},{"given":"Javier","family":"Iglesias-Fern\u00e1ndez","sequence":"additional","affiliation":[]},{"given":"Gon\u00e7alo J. 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