Molecular Determinants of Sequence-Dependent N-glycosylation by the Human Oligosaccharyltransferase
Protein N-glycosylation is catalysed by the oligosaccharyltransferase (OST) complex, yet how local sequon composition controls substrate selection by human OST remains poorly understood. Here we combine atomistic molecular dynamics, alchemical free-energy calculations, in cellulo glycosylation assays and human glycoproteome analysis to define the molecular basis of sequence-dependent…
The molecular determinants of sequence-dependent N-glycosylation by the human oligosaccharyltransferase (OST) complex are being investigated through a combination of advanced computational methods and experimental analyses. Researchers have constructed the first atomistic model of human OST, incorporating both the lipid-linked oligosaccharide donor and an acceptor peptide within a catalytically competent complex.
Simulations reveal that conserved STT3 motifs stabilize the acceptor Asn, explaining how substitutions at positions 0, +1, and +2 impact binding and productive geometry. Cellular assays in HEK 293T cells confirm the predicted loss of glycosylation for specific sequons, including N0Q, +1 Pro, and the +2 hierarchy Thr-Ser-Cys pattern.
The analysis of 14,800 human glycosites supports these rules at a proteome scale, shedding light on the molecular basis of sequence-dependent N-glycosylation by the human OST complex.
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