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 Companõn; Helena Coelho; Ana Diniz; Jesús Jiménez-Barbero; Jesús M. Peregrina; Henrik Clausen; Francisco Corzana; Filipa Marcelo; Gonzalo Jiménez-Osés; Thomas A. Gerken; Ramon Hurtado-Guerrero

doi:10.1038/s41467-017-02006-0

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 Companõn, Helena Coelho, Ana Diniz, Jesús Jiménez-Barbero, Jesús M. Peregrina, Henrik Clausen, Francisco Corzana, Filipa Marcelo, Gonzalo Jiménez-Osés, Thomas A. Gerken, Ramon Hurtado-Guerrero^*

^*Corresponding author for this work

Glycomics Program

22 Citations (Scopus)

50 Downloads (Pure)

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- A nd/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.

Original language	English
Article number	1959
Journal	Nature Communications
Volume	8
Issue number	1
Number of pages	11
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-017-02006-0
Publication status	Published - Dec 2017

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The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferencesFinal published version, 1.6 MBLicence: CC BY

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Rivas, M. D. L., Lira-Navarrete, E., Daniel, E. J. P., Companõn, I., Coelho, H., Diniz, A., Jiménez-Barbero, J., Peregrina, J. M., Clausen, H., Corzana, F., Marcelo, F., Jiménez-Osés, G., Gerken, T. A., & Hurtado-Guerrero, R. (2017). The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferences. Nature Communications, 8(1), Article 1959. https://doi.org/10.1038/s41467-017-02006-0

Rivas, MDL, Lira-Navarrete, E, Daniel, EJP, Companõn, I, Coelho, H, Diniz, A, Jiménez-Barbero, J, Peregrina, JM, Clausen, H, Corzana, F, Marcelo, F, Jiménez-Osés, G, Gerken, TA & Hurtado-Guerrero, R 2017, 'The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferences', Nature Communications, vol. 8, no. 1, 1959. https://doi.org/10.1038/s41467-017-02006-0

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

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- A nd/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.",

author = "Rivas, {Matilde De Las} and Erandi Lira-Navarrete and Daniel, {Earnest James Paul} and Ismael Compan{\~o}n and Helena Coelho and Ana Diniz and Jes{\'u}s Jim{\'e}nez-Barbero and Peregrina, {Jes{\'u}s M.} and Henrik Clausen and Francisco Corzana and Filipa Marcelo and Gonzalo Jim{\'e}nez-Os{\'e}s and Gerken, {Thomas A.} and Ramon Hurtado-Guerrero",

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AU - Rivas, Matilde De Las

AU - Lira-Navarrete, Erandi

AU - Daniel, Earnest James Paul

AU - Companõn, Ismael

AU - Coelho, Helena

AU - Diniz, Ana

AU - Jiménez-Barbero, Jesús

AU - Peregrina, Jesús M.

AU - Clausen, Henrik

AU - Corzana, Francisco

AU - Marcelo, Filipa

AU - Jiménez-Osés, Gonzalo

AU - Gerken, Thomas A.

AU - Hurtado-Guerrero, Ramon

PY - 2017/12

Y1 - 2017/12

N2 - 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- A nd/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.

AB - 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- A nd/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.

U2 - 10.1038/s41467-017-02006-0

DO - 10.1038/s41467-017-02006-0

M3 - Journal article

C2 - 29208955

AN - SCOPUS:85037122538

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1959

ER -

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

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