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| Identification of the receptor component of the I kappa B alpha-ubiquitin ligase |
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| Author(s): Yaron A, Hatzubai A, Davis M, Lavon I, Amit S, Manning AM, Andersen JS, Mann M, Mercurio F, Ben-Neriah Y |
| Source: NATURE Volume: 396 Issue: 6711 Pages: 590-594 Published: DEC 10 1998 |
| Times Cited: 357 References: 26 |
| Abstract: NF-kappa B, a ubiquitous, inducible transcription factor involved in immune, inflammatory, stress and developmental processes, is retained in a latent form in the cytoplasm of non-stimulated cells by inhibitory molecules, I kappa Bs(1-3). It, activation is a paradigm for a signal-transduction cascade that integrates an inducible kinase and the ubiquitin-proteasome system to eliminate inhibitory regulators. Here we isolate the pI kappa B alpha-ubiquitin ligase (pI kappa B alpha-E3) that attaches ubiquitin, a small protein which marks other proteins for degradation by the proteasome system, to the phosphorylated NF-kappa B inhibitor pI kappa B alpha. Taking advantage of its high affinity to pI kappa B alpha, we isolate this ligase from HeLa cells by single-step immunoaffinity purification. Using nanoelectrospray mass spectrometry, we identify the specific component of the ligase that recognizes the pI kappa B alpha degradation motif as an F-box/WD-domain protein belonging to a recently distinguished family of beta-TrCP/Slimb proteins. This component, which we denote E3RS(I kappa B) (pI kappa B alpha-E3 receptor subunit), binds specifically to pI kappa B alpha and promotes its in vitro ubiquitination in the presence of two other ubiquitin-system enzymes, El and UBC5C, one of many known E2 enzymes. An F-box-deletion mutant of E3RS(I kappa B), which tightly binds pI kappa B alpha but does not support its ubiquitination, acts in vivo as a dominant-negative molecule, inhibiting the degradation of pI kappa B alpha and consequently NF-kappa B activation. E3RS(I kappa B) represents a family of receptor proteins that are core components of a class of ubiquitin ligases. When these receptor components recognize their specific ligand, which is a conserved, phosphorylation-based sequence motif, they target regulatory proteins containing this motif for proteasomal degradation. |
| Document Type: Article |
| Language: English |
| Reprint Address: Ben-Neriah, Y (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Immunol, IL-91120 Jerusalem, Israel |
Addresses:
1. Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Immunol, IL-91120 Jerusalem, Israel
2. Signal Pharmaceut Inc, San Diego, CA 92121 USA
3. Protana AS, DK-5230 Odense, Denmark |
| Publisher: MACMILLAN MAGAZINES LTD, PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 147AY |
| ISSN: 0028-0836 |
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