Structural basis of substrate recognition and catalysis by fucosyltransferase 8
Details
Publication Year 2020-05-08, Volume 295, Issue #19, Page 6677-6688
Journal Title
Journal of Biological Chemistry
Abstract
Fucosylation of the inner-most N-acetylglucosamine (GlcNAc) of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, the development of monoclonal antibody therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well characterized and provide a framework for understanding N-glycan maturation in the Golgi; however the structural basis for these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here, we describe several structures of mouse and human FUT8 in the apo state and in complex with guanosine diphosphate (GDP), a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80-2.50 A resolutions. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.
Publisher
ASBMB
WEHI Research Division(s)
Chemical Biology; Advanced Technology And Biology
PubMed ID
32220931
Open Access at Publisher's Site
https://doi.org/10.1074/jbc.RA120.013291
NHMRC Grants
NHMRC/1139549
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-04-07 01:20:07
Last Modified: 2021-05-12 08:29:06
An error has occurred. This application may no longer respond until reloaded. Reload 🗙