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ERAD: mechanism and physiolgcial function
Author(s) -
Hampton Randolph Y.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.98.2
Subject(s) - sterol , endoplasmic reticulum associated protein degradation , microbiology and biotechnology , ubiquitin , transmembrane protein , biology , transmembrane domain , biochemistry , chemistry , receptor , cholesterol , gene
The HRD pathway degrades a large variety of misfolded lumenal and transmembrane ER proteins. We study how the normal protein Hmg2, an isozyme of HMG‐CoA reductase undergoes regulated HRD pathway degradation, to better understand both cellular measurement of sterol pathway activity and the mechanisms the underlie ERAD. Entry of Hmg2 into the HRD quality control pathway is regulated by cellular levels of the sterol pathway molecule FPP, and the Hmg2p transmembrane domain is required for FPP‐regulated degradation. The TMD has an embedded motif known as the SSD, or sterol sensing domain, found in mammalian HMGR and other sterol‐pertinent proteins. Although this motif is most often implicated in the recognition of of sterols, it is clear for Hmg2p that FPP mediated HRD pathway entry depends on the SSD, suggesting that the motif is required for recognition of this non‐sterol signal. To understand regulated Hmg2p ubiquitination, and subsequent extraction from the ER membrane we have devised in vivo and in vitro approaches to study the biochemical requirements and the underlying mechanisms. Both HRD dependent ubiquitination and Cdc48‐dependent retrotranslocation are tractable for in vitro analysis, and allow evaluation of current models and discovery of new features of regulated Hmg2p degradation. The status of these studies will be discussed and integrated into our current models of regulated ER quality control.