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A proactive role of water molecules in acceptor recognition by protein O-fucosyltransferase 2

AuthorsValero-González, Jessika; Leonhard-Melief, Christina; Lira-Navarrete, Erandi; Jiménez-Osés, Gonzalo CSIC ORCID; Hernández-Ruiz, Cristina; Pallarés, María Carmen; Yruela Guerrero, Inmaculada CSIC ORCID ; Vasudevan,Deepika; Lostao, Anabel; Corzana, Francisco; Takeuchi, Hideyuki; Haltiwanger, Robert S; Hurtado-Guerrero, Ramon
X-ray crystallography
Issue Date2016
PublisherNature Publishing Group
CitationValero-González J, Leonhard-Melief C, Lira-Navarrete E, Jiménez-Osés G, Hernández-Ruiz C, Pallarés MC, Yruela I, Vasudevan D, Lostao A, Corzana F, Takeuchi H, Haltiwanger RS, Hurtado-Guerrero R. A proactive role of water molecules in acceptor recognition by protein O-fucosyltransferase 2. Nature Chemical Biology 12 (4): 240- (2016)
AbstractProtein O-fucosyltransferase 2 (POFUT2) is an essential enzyme that fucosylates serine and threonine residues of folded thrombospondin type 1 repeats (TSRs). To date, the mechanism by which this enzyme recognizes very dissimilar TSRs has been unclear. By engineering a fusion protein, we report the crystal structure of Caenorhabditis elegans POFUT2 (CePOFUT2) in complex with GDP and human TSR1 that suggests an inverting mechanism for fucose transfer assisted by a catalytic base and shows that nearly half of the TSR1 is embraced by CePOFUT2. A small number of direct interactions and a large network of water molecules maintain the complex. Site-directed mutagenesis demonstrates that POFUT2 fucosylates threonine preferentially over serine and relies on folded TSRs containing the minimal consensus sequence C-X-X-S/T-C. Crystallographic and mutagenesis data, together with atomic-level simulations, uncover a binding mechanism by which POFUT2 promiscuously recognizes the structural fingerprint of poorly homologous TSRs through a dynamic network of water-mediated interactions.
Description69 Pags.- 4 Figs.- Supplementary Information (6 Suppl. Tabls.- 19 Suppl. Figs.). The definitive version is available at: http://www.nature.com/nchembio/index.html
Publisher version (URL)http://dx.doi.org/10.1038/nchembio.2019
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