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#ERAD

2 public questions tagged with this topic.

Protein Sorting and Trafficking

Which enzyme trims mannose residues to signal degradation of misfolded proteins?

Distinguishing proteins still capable of folding from terminally misfolded clients destined for destruction relies on slow enzymatic removal of mannose residues acting as molecular clock. ER mannosidase I and ER-degradation-enhancing α-mannosidase-like proteins EDEM1, EDEM2 and EDEM3, which are catalytically active despite name suggesting lectin, cleave specific α1-2 linked mannoses from outer branches of high-mannose N-glycan. Initial Man9 processed to Man8B isoform, then after prolonged ER residence to Man7, Man6 species lacking terminal mannose on C-branch, disfavoring interaction with regl

Ref: Mast & Ng, Crit Rev Biochem Mol Biol 47: 2012, Mannose Trimming Signals ERAD.

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Protein Sorting and Trafficking

ERAD (ER-associated degradation) primarily involves:

ER-associated degradation provides clearance mechanism for terminally misfolded or orphan unassembled subunits that cannot be rescued by chaperones. Commitment step involves N-glycan mannose trimming as timer: ER mannosidase I and EDEM1-3, homologous to yeast Htm1, remove specific α1-2 mannose residues from high-mannose precursor Man9GlcNAc2 generating Man7-Man5 species exposing α1-6 mannose recognized as degradation signal. Trimmed glycans bound by MRH domains of degradation lectins OS-9 and XTP3-B that deliver clients to membrane-integrated ubiquitination apparatus comprising scaffold Sel1L

Ref: Smith et al., J Biol Chem 286: 2011, ERAD Involving Mannosidase Trimming.

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