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INSIG: a broadly conserved transmembrane chaperone for sterol‐sensing domain proteins
Author(s) -
Flury Isabelle,
Garza Renee,
Shearer Alexander,
Rosen Johanna,
Cronin Stephen,
Hampton Randolph Y
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600855
Subject(s) - biology , chaperone (clinical) , transmembrane domain , transmembrane protein , conserved sequence , sterol , membrane protein , microbiology and biotechnology , computational biology , biochemistry , peptide sequence , amino acid , membrane , cholesterol , gene , receptor , medicine , pathology
INSIGs are proteins that underlie sterol regulation of the mammalian proteins SCAP (SREBP cleavage activating protein) and HMG‐CoA reductase (HMGR). The INSIGs perform distinct tasks in the regulation of these effectors: they promote ER retention of SCAP, but ubiquitin‐mediated degradation of HMGR. Two questions that arise from the discovery and study of INSIGs are: how do they perform these distinct tasks, and how general are the actions of INSIGs in biology? We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol‐sensing domain (SSD)‐containing transmembrane region. Nsg1p functions naturally to limit degradation of Hmg2p when both proteins are at native levels, indicating a long‐standing functional interplay between these two classes of proteins. One way to unify the known, disparate actions of INSIGs is to view them as known adaptations of a chaperone dedicated to SSD‐containing client proteins.