Flexible regions within I{kappa}B{alpha} create the ubiquitin-independent degradation signal.
Homeostatic regulation of NF-κB requires the continuous synthesis of IκBα and its rapid degradation by the proteasome through a ubiquitin-independent pathway. We previously showed that the ubiquitin-independent degradation signal of unbound IκBα was located in the C-terminal PEST region, and we have now identified a single tyrosine, Tyr-289, and determined that the hydrophobic character of the tyrosine is important for the rapid turnover of IκBα. The sequence composition of the PEST peptide surrounding this Tyr-289 imposes a distinct polyproline II conformation. Enhancing the polyproline II helix formation correlates with slower degradation rates of unbound IκBα. We have further identified a degradation signal located within the 5th ankyrin repeat that is functional once the C terminus is removed. Both the C-terminal and 5th ankyrin repeat degradation signals have inherent flexibility and specific hydrophobic residue(s), which together constitute the ubiquitin-independent degradation signal for IκBα.
Mathes
Erika
E
From the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093.
Wang
Lily
L
From the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093.
Komives
Elizabeth
E
From the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093.
Ghosh
Gourisankar
G
From the Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093. Electronic address: gghosh@ucsd.edu.
D016475:3T3 Cells; D000818:Animals; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D025801:Ubiquitin
D020672:I-kappa B Proteins; C000606205:Nfkbia protein, mouse; D010455:Peptides; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; C011083:polyproline