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 ER...

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Bibliographic Details
Published in:Molecular cell 2009-04, Vol.34 (2), p.212-222
Main Authors: Sato, Brian K., Schulz, Daniel, Do, Phong H., Hampton, Randolph Y.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution
ATP-Binding Cassette Transporters - metabolism
Binding Sites
Endoplasmic Reticulum - metabolism
Membrane Proteins - metabolism
Membrane Transport Proteins
Molecular Sequence Data
Phenotype
Protein Folding
Protein Structure, Tertiary
PROTEINS
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - chemistry
Saccharomyces cerevisiae Proteins - metabolism
Saccharomyces cerevisiae Proteins - physiology
SEC Translocation Channels
Substrate Specificity - physiology
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
Ubiquitin-Protein Ligases - physiology
Ubiquitination
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Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2009.03.010