Protein dislocation from the ER

Abstract

Protein folding within the endoplasmic reticulum (ER) of eukaryotic cells is erroneous and often results in the formation of terminally malfolded species. A quality control system retards such molecules in the ER and eventually initiates their dislocation into the cytosol for proteolysis by 26S proteasomes. This process is termed ER associated protein degradation (ERAD). The spatial separation of ER based quality control and cytosolic proteolysis poses the need for a machinery that promotes the extraction of substrates from the ER. Due to the heterogeneous nature of the client proteins this transport system displays several unique features. Selective recognition of ERAD substrates does not involve transferable transport signals in the primary sequence and thus must follow other principles than established for proteins designated for the import into organelles. Moreover, an ER dislocation system must be capable to ship polypeptides, which may be at least partly folded and are in most cases covalently modified with bulky and hydrophilic glycans, through a membrane without disrupting the integrity of the ER. In this review we present current ideas on the highly dynamic and flexible nature of the dislocation apparatus and speculate on the mechanism that removes aberrant polypeptides from the ER in the course of ERAD. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes.

Protein Folding and Quality Control in the ER

“…Thus far, E3 ligase complexes are the predominant candidates because they constitute large protein complexes containing multispanning membrane proteins such as HRD1 and Derlin-1, which can efficiently recognize, target, retrotranslocate, and ubiquitinate ERAD substrates within the organized complexes (Fig. 2) (Bagola et al 2011).…”

Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy

“…Interestingly, the proposed role for Pex1 and Pex6 in peroxisomal protein import is similar to that of p97 in ERAD (35). In ERAD, p97 cooperates with the cofactors Ufd1 and Npl4 to extract ubiquitinated proteins from the ER membrane (36,37), and similarly, Pex1 and Pex6 are thought to recycle ubiquitinated import receptor Pex5 by extracting it from the peroxisomal membrane (35).…”

Sequential Actions of the AAA-ATPase Valosin-containing Protein (VCP)/p97 and the Proteasome 19 S Regulatory Particle in Sterol-accelerated, Endoplasmic Reticulum (ER)-associated Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

“…However, a major difference exists in the mechanism for membrane extraction and cytosolic dislocation of reductase and s: proteolytic activity of proteasomes is required for dislocation of s, whereas reductase dislocation can only be observed upon proteasome inhibition. Proteasome inhibition is known to cause several membrane-bound ERAD substrates in addition to reductase to accumulate in the cytosol of cells (13,(41)(42)(43)(44)(45)(46)(47). It will thus be important to determine in future studies whether membrane extraction and release into the cytosol through sequential actions of VCP/p97 and the proteasome 19 S RP are a general ERAD mechanism or a peculiarity in the sterol-accelerated ERAD of reductase.…”

“…* This work was supported, in whole or in part, by National Institutes of Health A key event in the ERAD pathway is dislocation of substrates from ER membranes into the cytosol where they become fully accessible to proteasomes for degradation. Although cytosolic dislocation has been demonstrated for both soluble substrates sequestered within the ER lumen and membrane-bound substrates with one or more membrane-spanning segments (1,13), underlying mechanisms for the reaction remain to be completely elucidated. Previous studies showed that sterols cause intact, full-length reductase to become dislocated from ER membranes into the cytosol (14,15).…”