2. Academic Validation
  3. Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation

Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation

  • Nat Commun. 2015 May 5;6:6937. doi: 10.1038/ncomms7937.
Erandi Lira-Navarrete 1,  Matilde de Las Rivas 1,  Ismael Compañón 2,  María Carmen Pallarés 3,  Yun Kong 4,  Javier Iglesias-Fernández 5,  Gonçalo J L Bernardes 6,  Jesús M Peregrina 2,  Carme Rovira 7,  Pau Bernadó 8,  Pierpaolo Bruscolini 9,  Henrik Clausen 4,  Anabel Lostao 10,  Francisco Corzana 2,  Ramon Hurtado-Guerrero 11
Affiliations

Affiliations

  • 1 BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza 50018, Spain.
  • 2 Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, E-26006 Logroño, Spain.
  • 3 LMA, INA, Universidad de Zaragoza, 50018 Zaragoza, Spain.
  • 4 Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, School of Dentistry, University of Copenhagen, Copenhagen DK-2200, Denmark.
  • 5 Departament de Química Orgànica i IQTCUB, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
  • 6 1] Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK [2] Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028 Lisboa, Portugal.
  • 7 1] Departament de Química Orgànica i IQTCUB, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain [2] ICREA, Passeig Lluís Companys 23, 08020 Barcelona, Spain.
  • 8 Centre de Biochimie Structurale, INSERM U1054, CNRS UMR 5048, Université Montpellier 1 and 2, 29 rue de Navacelles, 34090 Montpellier, France.
  • 9 1] BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza 50018, Spain [2] Departamento de Física Teórica, Universidad de Zaragoza, Zaragoza 50009, Spain.
  • 10 1] LMA, INA, Universidad de Zaragoza, 50018 Zaragoza, Spain [2] Fundación ARAID, 50018 Zaragoza, Spain.
  • 11 1] BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza 50018, Spain [2] Fundación ARAID, 50018 Zaragoza, Spain.
PMID: 25939779 DOI: 10.1038/ncomms7937
Abstract

Protein O-glycosylation is controlled by polypeptide GalNAc-transferases (GalNAc-Ts) that uniquely feature both a catalytic and lectin domain. 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 O-glycans.

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