Glycosylation-directed quality control of protein folding

Abstract

Membrane-bound and soluble proteins of the secretory pathway are commonly glycosylated in the endoplasmic reticulum. These adducts have many biological functions, including, notably, their contribution to the maturation of glycoproteins. N-linked glycans are of oligomeric structure, forming configurations that provide blueprints to precisely instruct the folding of protein substrates and the quality control systems that scrutinize it. O-linked mannoses are simpler in structure and were recently found to have distinct functions in protein quality control that do not require the complex structure of N-linked glycans. Together, recent studies reveal the breadth and sophistication of the roles of these glycan-directed modifications in protein biogenesis.

O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking

“…Glycosylation in the endoplasmic reticulum (ER) 4 has long been associated with protein folding (1,2). Oligosaccharyltransferase modifies newly synthesized proteins as they emerge in the lumen of the ER with N-glycans that are trimmed and recognized by calnexin/calreticulin chaperones, allowing a round of protein folding.…”

Human Plasma N-glycosylation as Analyzed by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance-MS Associates with Markers of Inflammation and Metabolic Health

“…Examples include quality control during protein folding, regulation of circulatory half-life, and modulation of receptor interactions by either providing the recognition motif or by affecting protein conformation (1)(2)(3)(4)(5)(6)(7). Consequentially, glycosylation has been associated with a multitude of diseases and states thereof, among which the progression and metastasis of cancer and the remission of rheumatoid arthritis (8 -11).…”

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

“…If multiple refolding attempts do not result in a correctly folded protein, the ER-associated degradation machinery retrotranslocates the protein back into the cytosol, where it is processed for proteosomal degradation. 37,38 Correctly folded proteins then transit via the cis-, medial-, and trans-Golgi compartments for additional processing and sequential modifications to the glycan chain. Mannose trimming occurs in the cis-Golgi compartment after which the glycoconjugate is branched by N-acetyl glucoseaminotransferases (GnTs) in the medial Golgi.…”