Misfolded membrane proteins are specifically recognized by the transmembrane domain of the Hrd1p ubiquitin ligase.

Quality control pathways such as ER-associated degradation (ERAD) employ a small number of factors to specifically recognize a wide variety of protein substrates. Delineating the mechanisms of substrate selection is a principle goal in studying quality control. The Hrd1p ubiquitin ligase mediates ERAD of numerous misfolded proteins including soluble, lumenal ...
ERAD-L and membrane-anchored ERAD-M substrates. We tested if the Hrd1p multispanning membrane domain was involved in ERAD-M specificity. In this work, we have identified site-directed membrane domain mutants of Hrd1p impaired only for ERAD-M and normal for ERAD-L. Furthermore, other Hrd1p variants were specifically deficient for degradation of individual ERAD-M substrates. Thus, the Hrd1p transmembrane region bears determinants of high specificity in the ERAD-M pathway. From in vitro and interaction studies, we suggest a model in which the Hrd1p membrane domain employs intramembrane residues to evaluate substrate misfolding, leading to selective ubiquitination of appropriate ERAD-M clients.
Mesh Terms:
ATP-Binding Cassette Transporters, Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Endoplasmic Reticulum, Membrane Proteins, Membrane Transport Proteins, Molecular Sequence Data, Phenotype, Protein Folding, Protein Structure, Tertiary, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Substrate Specificity, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell
Date: Apr. 24, 2009
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