Structural basis for substrate specificity and catalysis of a1,6-fucosyltransferase

García-García, Ana (Universidad de Zaragoza) ; Ceballos-Laita, Laura ; Serna, Sonia ; Artschwager, Raik ; Reichardt, Niels C. ; Corzana, Francisco ; Hurtado-Guerrero, Ramón (Universidad de Zaragoza)

Resumen: Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-ß-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme a1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an a-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an SN2 mechanism and deploys a series of loops and an a-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the a1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.

Idioma: Inglés

DOI: 10.1038/s41467-020-14794-z

Año: 2020

Publicado en: Nature Communications 11 (2020), 973 1-9
ISSN: 2041-1723

Factor impacto JCR: 14.919 (2020)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 4 / 73 = 0.055 (2020) - Q1 - T1

Factor impacto SCIMAGO: 5.559 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E34-R17
Financiación: info:eu-repo/grantAgreement/ES/DGA/LMP58-18
Financiación: info:eu-repo/grantAgreement/EC/FP7/283570/EU/Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities/BIOSTRUCT-X
Financiación: info:eu-repo/grantAgreement/ES/MICINN-AEI/MDM-2017-0720
Financiación: info:eu-repo/grantAgreement/ES/MICINN/RTI2018-099592-B-C21
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-75633-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2013-44367-C2-2-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2017-90039-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RTC-2017-6126-1

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)