Dr James W. Dennis
Lunenfeld-Tanenbaum Research Institute,
Departments of Molecular Genetics and
Laboratory Medicine and Pathology, Toronto
Invité par : Les étudiants de l’axe Endo-Néphro
Jeudi 15 décembre 2016
13h00
Amphithéâtre Fisher, Local TR-54, Site CHUL
«Golgi N-glycan biosynthesis links metabolism
with adaptation at the cell surface»
Posttranslational modifications (PTM) often act as weak docking sites for multivalent
adaptor proteins in the reversible formation of complexes that mediate information flow in
the cell. Of particular interest, N-glycosylation; notably Golgi N-glycan branching enzymes
(Mgat1,2,4 and 5) in the medial Golgi generates ligands for galectin binding. Galectins bind
to the branches (galactose1-4N-acetylglucosamine) in N-glycans and affinities are
proportional to branch number, as well as sequence-encoded NXS/T(X≠P) glycosylation
sites, an evolved feature of each glycoprotein. Galectins oligomerize, and multivalent
binding results in a dynamic lattice that regulates the residency-time of receptor kinases
and nutrient transporters at the cell surface. Our analysis of Mgat5 deficient mice revealed
adult phenotypes linked in part through metabolism, including delayed oncogene-induced
tumor progression, autoimmune sensitivity, reduced fecundity, depression-like behaviour,
resistance to weight-gain on high-fat diet, glucagon insensitivity, loss of adult stem cells and
early aging. Partial rescue is possible by supplementing with UDP-GlcNAc to (Mgat1, 2 and
4). N-glycan branching is sensitive to the levels of donor substrate UDP-GlcNAc, as well as
glucose, glutamine, acetyl-CoA and GlcNAc which supply UDP-GlcNAc biosynthesis. The
NXS/T site number in various signaling receptor interacts with N-glycan branching pathway
through its dependency on UDP-GlcNAc to regulate sensitivity to growth and arrest
cytokines. I will also discuss how we might advance our understanding by comparable
biophysical features of different PTM systems. Also how diverse molecular ensembles in
transiently bound states can display remarkable control of signaling.
Non disponible