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Structure and function of the EDEM:PDI ERAD checkpoint complex

Hitchman, C. J.; Lia, A.; Chiritoiu, G. N.; Munteanu, C. V. A.; Ortigosa, J.; Ghenea, S.; Savva, C. G.; De Benedictis, M.; Tax, G.; Bayo, Y.; Crescioli, I.; Alonzi, D. L.; Quigley, A.; Modenutti, C. P.; Petrescu, S. M.; Santino, A.; Gooptu, B.; Roversi, P.

2025-01-30 biochemistry
10.1101/2025.01.29.635535 bioRxiv
Show abstract

The ERAD glycoprotein misfolding checkpoint complex de-mannosylates misfolded glycoproteins to enable retrotranslocation, ubiquitination, and proteasomal degradation. The complex comprises an Endoplasmic Reticulum-Degradation Enhancing -Mannosidase (EDEM) and a Protein Disulfide Isomerase (PDI). We solved Cryo-EM structures of Chaetomium thermophilum (Ct) Ct EDEM:Ct PDI, both as the heterodimer with no client and in complex with 1-antitrypsin (A1AT-NHK). The EDEM catalytic domain nests within the PDI arc, while A1AT-NHK binds EDEMs C-terminal flexible domains. Mass spectrometry reveals a disulfide bond between A1AT-NHK and an exposed Cys in the PAD of the EDEM. Co-transfection of EDEM, A1AT-NHK, and PDI shifts EDEM:PDI to higher molecular weight in non-reducing SDS-PAGE. Redox chemistry between EDEM and PDI disulfide bonds generates oxidized, demannosylation-competent EDEM and reduced PDI, priming PDI to function as the ERAD reductase, facilitating client retrotranslocation.

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