Taking out the trash: How misfolded proteins are removed from the endoplasmic reticulum

Abstract

Proteins that are expressed on membrane surfaces or secreted are involved in all aspects of cellular and organismal life, and as such require extremely high fidelity during their synthesis and maturation. These proteins are synthesized at the endoplasmic reticulum (ER) where a dedicated quality control system (ERQC) ensures only properly matured proteins reach their destinations. An essential component of this process is the identification of proteins that fail to pass ERQC and their retrotranslocation to the cytosol for proteasomal degradation. This study by Wu et al. reports a cryo-electron microscopy (cryo-EM) structure of the five-protein channel through which aberrant proteins are extracted from the ER, providing insights into how recognition of misfolded proteins is coupled to their transport through a hydrophobic channel that acts to thin the ER membrane, further facilitating their dislocation to the cytosol¹.

Keywords: Cryo-EM; ERAD; Endoplasmic reticulum; Hrd1.

Figure 1. A model for the retrotranslocation of a misfolded ER luminal protein by the Hrd1 complex based on assembled cryo-EM structures

(A) Space-filling model was generated from cryo-EM structures of the yeast Hrd1 complex (PDB code 6VJZ) in which segments of the 5 subunits are depicted in different colors. The predicted interactions of a misfolded glycoprotein, shown schematically in green, with the MRH domain of Yos9 positioning an extended polypeptide segment at the groove present in Hrd3. (B) The various features of the Hrd1 complex identified by cryo-EM structures are compatible with the engaged client inserting as a hairpin loop into the channel formed by Hrd1 and Der1. (C) TM boundaries predict membrane thinning by the Der1 and Hrd1 components of the complex, which was supported by molecular dynamics simulations. Phospholipid molecules are shown schematically with head groups in green and acyl chains in grey. (D) As the client emerges in the cytosol, the Hrd1 ligase catalyzes the attachment of ubiquitin molecules, which are subsequently recognized by the Ufd1/Npl4 cofactor of the Cdc48 ATPase, which pulls it out of the ER membrane. This image was reproduced with kind permission from X. Wu and T. Rapoport.