N-glycosylation Triggers a Dual Selection Pressure in Eukaryotic Secretory Proteins

Abstract

Nearly one third of the eukaryotic proteome traverses the secretory pathway and most of these proteins are N-glycosylated in the lumen of the endoplasmic reticulum. N-glycans fulfill multiple structural and biological functions, and are crucial for productive folding of many glycoproteins. N-glycosylation involves the attachment of an oligosaccharide to selected asparagine residues in the sequence N-X-S/T (X ≠ P), a motif known as an N-glycosylation’sequon’. Mutations that create novel sequons can cause disease due to the destabilizing effect of a bulky N-glycan. Thus, an analogous process must have occurred during evolution, whenever ancestrally cytosolic proteins were recruited to the secretory pathway. Here, we show that during evolution N-glycosylation triggered a dual selection pressure on secretory pathway proteins: while sequons were positively selected in solvent exposed regions, they were almost completely eliminated from buried sites. This process is one of the sharpest evolutionary signatures of secretory pathway proteins, and was therefore critical for the evolution of an efficient secretory pathway.

Human protein paucimannosylation: cues from the eukaryotic kingdoms

“…In eukaryotes, the reducing end of this constant core is linked to proteins through GlcNAcβ1‐Asn in canonical N ‐glycosylation sequons (NxS/T/C, x ≠ P) (Schwarz & Aebi, ; Aebi, ). The utilisation and the extent of glycan processing at each site are dictated by the local amino acid sequence and the three‐dimensional conformation around each glycosylation site, giving rise to site‐specific glycosylation (Ben‐Dor et al ., ; Thaysen‐Andersen & Packer, ; Lee et al ., ; Medus et al ., ).…”

Resolving the TorsinA Oligomerization Conundrum: The Glycan Hypothesis

“…N -linked glycans are usually studied in the context of protein quality control during folding and biogenesis, of genetic diseases, and due to their role in immunological responses and microbial pathogenesis. However, it is becoming increasingly clear that the occupancy and structural heterogeneity of the glycans play fundamental structural and physiological roles ( Higel et al, 2016 ; Zacchi and Schulz, 2016 ; Medus et al, 2017 ). Here, we highlight the key function of N -linked glycans in shaping the conformation and structure of protein complexes ( Medus et al, 2017 ), and hypothesize that their presence or absence dramatically impact torsinA oligomerization by introducing sterical restrictions.…”

“…Therefore, N -linked glycans are key post-translational modifications for torsinA biogenesis. N -linked glycans are bulky and hydrophilic molecules ( Varki, 2017 ) and, in addition to their role in folding and quality control, N -linked glycans can restrict the formation of quaternary structures in proteins ( Medus et al, 2017 ). This conformation-shaping effect has been well documented for immunoglobulin G ( Nagae and Yamaguchi, 2012 ; Higel et al, 2016 ).…”

Sialic Acid-Siglec Axis as Molecular Checkpoints Targeting of Immune System: Smart Players in Pathology and Conventional Therapy

“…More than 50 nine-carbon monosugars derived from neuraminic acid belong to the family of sialic acids, among which N-acety1-5-neuraminic acid also called sialic acid (SA, Neu5Ac, NANA) is the most common form found in cell membrane glycoproteins and body fluids [20]. The sialic acid is ubiquitously expressed, typically at the terminal position of glycoproteins and lipids in the glycosylation process, resulting in co-translational and posttranslational modifications of approximately 80% of cell proteins [21]. Sialylation as the final stage of glycosylation is based on the balance achieved by the expression and activity of sialyltransferases and sialidases involved in the decoration of sugar chains, and on the sialic acid precursors contained in nutrient resources, as well as the expression of several metabolic enzymes implicated in the synthesis and conversion of sialic acid molecules.…”