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

  1. Valero-González, J. 7
  2. Leonhard-Melief, C. 3
  3. Lira-Navarrete, E. 7
  4. Jiménez-Osés, G. 247
  5. Hernández-Ruiz, Cristina. 7
  6. Pallarés, M.C. 7
  7. Yruela, I. 5
  8. Vasudevan, D. 3
  9. Lostao, Anabel. 67
  10. Corzana, F. 2
  11. Takeuchi, H. 13
  12. Haltiwanger, R.S. 13
  13. Hurtado-Guerrero, R. 678
  1. 1 University of Georgia
    info

    University of Georgia

    Athens, Estados Unidos

    ROR https://ror.org/00te3t702

  2. 2 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  3. 3 Stony Brook University
    info

    Stony Brook University

    Stony Brook, Estados Unidos

    ROR https://ror.org/05qghxh33

  4. 4 University of California Los Angeles
    info

    University of California Los Angeles

    Los Ángeles, Estados Unidos

    ROR https://ror.org/046rm7j60

  5. 5 Estación Experimental de Aula Dei
    info

    Estación Experimental de Aula Dei

    Zaragoza, España

    ROR https://ror.org/056a37x91

  6. 6 Fundación Agencia Aragonesa Para la Investigación y Desarrollo (ARAID), Zaragoza, Spain
  7. 7 Universidad de Zaragoza
    info

    Universidad de Zaragoza

    Zaragoza, España

    ROR https://ror.org/012a91z28

  8. 8 Instituto de Investigación Sanitaria Aragón
    info

    Instituto de Investigación Sanitaria Aragón

    Zaragoza, España

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Revista:
Nature Chemical Biology

ISSN: 1552-4450

Año de publicación: 2016

Volumen: 12

Número: 4

Páginas: 240-246

Tipo: Artículo

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DOI: 10.1038/NCHEMBIO.2019 SCOPUS: 2-s2.0-84957678805 WoS: WOS:000372593200010 GOOGLE SCHOLAR

Otras publicaciones en: Nature Chemical Biology

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Resumen

Protein 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. © 2016 Nature America, Inc. All rights reserved.