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Proteasomal degradation of ubiquitinated Insig proteins is determined by serine residues flanking ubiquitinated lysines.

Insig-1 and Insig-2 are closely related proteins of the endoplasmic reticulum that play crucial roles in cholesterol homeostasis by inhibiting excessive cholesterol synthesis and uptake. In sterol-depleted cells Insig-1 is degraded at least 15 times more rapidly than Insig-2, owing to ubiquitination of Lys-156 and Lys-158 in Insig-1. In this study, we use domain-swapping methods to localize amino acid residues responsible for this differential degradation. In the case of Insig-2, Glu-214 stabilizes the protein by preventing ubiquitination. When Glu-214 is changed to alanine, Insig-2 becomes ubiquitinated, but it is still not degraded as rapidly as ubiquitinated Insig-1. The difference in the degradation rates is traced to two amino acids: Ser-149 in Insig-1 and Ser-106 in Insig-2. Ser-149, which lies NH(2)-terminal to the ubiquitination sites, accelerates the degradation of ubiquitinated Insig-1. Ser-106, which is COOH-terminal to the ubiquitination sites, retards the degradation of ubiquitinated Insig-2. The current studies indicate that the degradation of ubiquitinated Insigs is controlled by serine residues flanking the sites of ubiquitination.

Pubmed ID: 16549805


  • Lee JN
  • Gong Y
  • Zhang X
  • Ye J


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 28, 2006

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL-20948

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Conserved Sequence
  • Cricetinae
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysine
  • Membrane Proteins
  • Molecular Sequence Data
  • Mutation
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Sequence Alignment
  • Serine
  • Ubiquitin