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Mol Cell. 2009 Apr 24;34(2):212-22. doi: 10.1016/j.molcel.2009.03.010.

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

Author information

1
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Abstract

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.

PMID:
19394298
PMCID:
PMC2710143
DOI:
10.1016/j.molcel.2009.03.010
[Indexed for MEDLINE]
Free PMC Article

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