Modulation of ERQC and ERAD: A Broad-Spectrum Spanner in the Works of Cancer Cells?

Figure 1

Structural view of ERQC/ERAD. The ER trajectory of the folding stages of a glycoprotein, bound to a glycan of variable composition, is followed through its interactions with ERQC/ERAD components, either ER-lumenal or ER-membrane associated. Proteins whose structures have been described in the literature for at least one eukaryotic species are in cartoon representation, while homology models of proteins of unknown structure are in semitransparent surface representation. Proteins for which no orthologue of known structure exists are represented as arbitrary 2D shapes. The red squiggly symbol represents the polypeptidic part of a glycoprotein on its way to folding (either incompletely folded, transiently misfolded, or terminally misfolded), while the red helix and two-stranded-β-sheet symbol represents a glycoprotein that has successfully attained its native fold. The symbols of the monosaccharides in the glycan are from [151]: blue squares, N-acetyl glucosamine (GlcNAc); green circles, mannose (Man); blue circles, glucose (Glc). The symbolic N-linked glycan on the glycoprotein is not to scale with the proteins, and the proteins themselves are not represented to exact relative scale to one another. The nascent glycoprotein in the upper-left corner has just been synthesised into the ER by a translocon-associated ribosome. After translation/translocation, the polypeptide has been glycosylated by oligosaccharyl-transferase (OST, not shown) and carries a GlcNAc₂Man₉Glc₃ glycan. The nascent glycoprotein is first deglucosylated by GCS1 (purple, mouse GCS1, PDB ID 5MHF, on the left), which leaves a GlcNAc₂Man₉Glc₂ glycan; a further deglucosylation step by ER αGluII (mouse GCS2, green and cyan, PDB ID 5F0E) produces a GlcNAc₂Man₉Glc₁ glycan, through which the glycoprotein can associate with the lectin domain of either calnexin (CNX, indigo, dog calnexin, PDB ID 1JHN) or calreticulin (not shown) and the associated foldases/chaperones (not shown). A second cleavage by ER αGluII leaves a GlcNAc₂Man₉ glycan on the glycoprotein, which can bind no longer to the ER lectins and if folded is free to progress to the Golgi and beyond (upper right corner). If the glycoprotein fold is not native yet, the misfolded glycoprotein is recognised and reglucosylated by UGGT (orange, CtUGGT, PDB ID 5NV4), using UDP-Glc as a source of glucose. The resulting GlcNAc₂Man₉Glc₁ glycoprotein can reassociate with the CNX/CRT to profit from further attempts at chaperone/foldase-assisted folding. The UGGT partner protein Sep15 is in salmon pink (triangle: Nterm domain; surface: Cterm domain). The UDP molecule produced by UGGT-mediated reglucosylation is hydrolysed by a ER UDPase (grey) to inorganic phosphate (P_i) and UMP—the latter being antiported back to the cytoplasm by an ER-membrane-resident ER UDP-Glc transporter (cyan), in exchange for a molecule of UDP-Glc. Terminally misfolded glycoproteins are first demannosylated by ER αManI (magenta, PDB ID 1X9D) and then by EDEM1 (wheat), to yield a GlcNAc₂Man_5–7 glycan. The mannose-6-phosphate receptor homology (MRH) domain of OS-9 (yellow) binds the demannosylated glycan and recruits the terminally misfolded glycoprotein to the ERAD retrotranslocon assembled around the HRD1/HRD3 ubiquitin ligase (magenta, violet, green and cyan, yeast structures, PDB IDs 5V6P and 5V7V, on the right). A cytoplasmic proteasome then degrades the terminally misfolded ubiquitinated glycoprotein (not shown).