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Nature Research, Nature Communications, 1(6), 2015

DOI: 10.1038/ncomms7937

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

Journal article published in 2015 by Erandi Lira-Navarrete, Matilde de Las Rivas, Matilde Teresa De Las Rivas González De Garay, M. De Las Rivas, Ismael Compañón, María Carmen Pallarés, Yun Kong, Javier Iglesias-Fernández, Gonçalo J. L. Bernardes ORCID, Jesús M. Peregrina ORCID, Carme Rovira ORCID, Pau Bernadó, Pierpaolo Bruscolini, Henrik Clausen, Anabel Lostao ORCID and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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. ; Peer Reviewed