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; Ramon Hurtado-Guerrero

doi:10.1038/ncomms7937

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, Ramon Hurtado-Guerrero

Glycomics Program

54 Citations (Scopus)

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.

Original language	English
Article number	6937
Journal	Nature Communications
Volume	6
Number of pages	12
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms7937
Publication status	Published - 5 May 2015

Access to Document

10.1038/ncomms7937Licence: CC BY

Cite this

Lira-Navarrete, E., de Las Rivas, M., Compañón, I., Pallarés, M. C., Kong, Y., Iglesias-Fernández, J., Bernardes, G. J. L., Peregrina, J. M., Rovira, C., Bernadó, P., Bruscolini, P., Clausen, H., Lostao, A., Corzana, F., & Hurtado-Guerrero, R. (2015). Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation. Nature Communications, 6, [6937]. https://doi.org/10.1038/ncomms7937

Lira-Navarrete, E, de Las Rivas, M, Compañón, I, Pallarés, MC, Kong, Y, Iglesias-Fernández, J, Bernardes, GJL, Peregrina, JM, Rovira, C, Bernadó, P, Bruscolini, P, Clausen, H, Lostao, A, Corzana, F & Hurtado-Guerrero, R 2015, 'Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation', Nature Communications, vol. 6, 6937. https://doi.org/10.1038/ncomms7937

@article{6f4e7c2b80c04cb0a151f871cb48b81e,

title = "Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation",

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.",

author = "Erandi Lira-Navarrete and {de Las Rivas}, Matilde and Ismael Compa{\~n}{\'o}n and Pallar{\'e}s, {Mar{\'i}a Carmen} and Yun Kong and Javier Iglesias-Fern{\'a}ndez and Bernardes, {Gon{\c c}alo J L} and Peregrina, {Jes{\'u}s M} and Carme Rovira and Pau Bernad{\'o} and Pierpaolo Bruscolini and Henrik Clausen and Anabel Lostao and Francisco Corzana and Ramon Hurtado-Guerrero",

year = "2015",

month = may,

day = "5",

doi = "10.1038/ncomms7937",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

}

TY - JOUR

T1 - Dynamic interplay between catalytic and lectin domains of GalNAc-transferases modulates protein O-glycosylation

AU - Lira-Navarrete, Erandi

AU - de Las Rivas, Matilde

AU - Compañón, Ismael

AU - Pallarés, María Carmen

AU - Kong, Yun

AU - Iglesias-Fernández, Javier

AU - Bernardes, Gonçalo J L

AU - Peregrina, Jesús M

AU - Rovira, Carme

AU - Bernadó, Pau

AU - Bruscolini, Pierpaolo

AU - Clausen, Henrik

AU - Lostao, Anabel

AU - Corzana, Francisco

AU - Hurtado-Guerrero, Ramon

PY - 2015/5/5

Y1 - 2015/5/5

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms7937

DO - 10.1038/ncomms7937

M3 - Journal article

C2 - 25939779

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6937

ER -

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

Abstract

Access to Document

Fingerprint

Cite this