The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferences

Matilde de las Rivas, Erandi Lira-Navarrete, Earnest James Paul Daniel, Ismael Compañón, Helena Coelho, Ana Diniz, Jesús Jiménez-Barbero, Jesús M. Peregrina, Henrik Clausen, Francisco Corzana, Filipa Marcelo, Gonzalo Jiménez-Osés, Thomas A. Gerken and Ramon Hurtado-Guerrero ()
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Matilde de las Rivas: BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D
Erandi Lira-Navarrete: BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D
Earnest James Paul Daniel: Case Western Reserve University
Ismael Compañón: Universidad de La Rioja, Centro de Investigación en Síntesis Química
Helena Coelho: Faculdade de Ciências e Tecnologia, Universidade de Nova de Lisboa
Ana Diniz: Faculdade de Ciências e Tecnologia, Universidade de Nova de Lisboa
Jesús Jiménez-Barbero: CIC bioGUNE, Bizkaia Technology Park
Jesús M. Peregrina: Universidad de La Rioja, Centro de Investigación en Síntesis Química
Henrik Clausen: University of Copenhagen
Francisco Corzana: Universidad de La Rioja, Centro de Investigación en Síntesis Química
Filipa Marcelo: Faculdade de Ciências e Tecnologia, Universidade de Nova de Lisboa
Gonzalo Jiménez-Osés: Universidad de La Rioja, Centro de Investigación en Síntesis Química
Thomas A. Gerken: Case Western Reserve University
Ramon Hurtado-Guerrero: BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The polypeptide GalNAc-transferases (GalNAc-Ts), that initiate mucin-type O-glycosylation, consist of a catalytic and a lectin domain connected by a flexible linker. In addition to recognizing polypeptide sequence, the GalNAc-Ts exhibit unique long-range N- and/or C-terminal prior glycosylation (GalNAc-O-Ser/Thr) preferences modulated by the lectin domain. Here we report studies on GalNAc-T4 that reveal the origins of its unique N-terminal long-range glycopeptide specificity, which is the opposite of GalNAc-T2. The GalNAc-T4 structure bound to a monoglycopeptide shows that the GalNAc-binding site of its lectin domain is rotated relative to the homologous GalNAc-T2 structure, explaining their different long-range preferences. Kinetics and molecular dynamics simulations on several GalNAc-T2 flexible linker constructs show altered remote prior glycosylation preferences, confirming that the flexible linker dictates the rotation of the lectin domain, thus modulating the GalNAc-Ts' long-range preferences. This work for the first time provides the structural basis for the different remote prior glycosylation preferences of the GalNAc-Ts.

Date: 2017
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DOI: 10.1038/s41467-017-02006-0

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