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

Erandi Lira-Navarrete, Matilde de las Rivas, Ismael Compañón, María Carmen Pallarés, Yun Kong, Javier Iglesias-Fernández, Gonçalo J. L. Bernardes, Jesús M. Peregrina, Carme Rovira, Pau Bernadó, Pierpaolo Bruscolini, Henrik Clausen, Anabel Lostao, Francisco Corzana and Ramon Hurtado-Guerrero ()
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Erandi Lira-Navarrete: BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n
Matilde de las Rivas: BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n
Ismael Compañón: Universidad de La Rioja, Centro de Investigación en Síntesis Química
María Carmen Pallarés: LMA, INA, Universidad de Zaragoza
Yun Kong: Copenhagen Center for Glycomics, School of Dentistry, University of Copenhagen
Javier Iglesias-Fernández: Departament de Química Orgànica i IQTCUB, Universitat de Barcelona
Gonçalo J. L. Bernardes: University of Cambridge
Jesús M. Peregrina: Universidad de La Rioja, Centro de Investigación en Síntesis Química
Carme Rovira: Departament de Química Orgànica i IQTCUB, Universitat de Barcelona
Pau Bernadó: Centre de Biochimie Structurale, INSERM U1054, CNRS UMR 5048, Université Montpellier 1 and 2
Pierpaolo Bruscolini: BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n
Henrik Clausen: Copenhagen Center for Glycomics, School of Dentistry, University of Copenhagen
Anabel Lostao: LMA, INA, Universidad de Zaragoza
Francisco Corzana: Universidad de La Rioja, Centro de Investigación en Síntesis Química
Ramon Hurtado-Guerrero: BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7937

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DOI: 10.1038/ncomms7937

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