| Structural highlights
Function
FBW1A_HUMAN Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds to phosphorylated target proteins. SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling. SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22'. SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1/nuclear factor NF-kappa-B p105 subunit, ATF4, SMAD3, SMAD4, CDC25A, DLG1, FBXO5 and probably NFKB2. SCF(BTRC) mediates the ubiquitination of phosphorylated SNAI1. May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
Eukaryotic cell biology depends on cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation(1), which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8(2-6). However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1(beta-TRCP) promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated IkappaBalpha. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin-RING proteins.
NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly.,Baek K, Krist DT, Prabu JR, Hill S, Klugel M, Neumaier LM, von Gronau S, Kleiger G, Schulman BA Nature. 2020 Feb;578(7795):461-466. doi: 10.1038/s41586-020-2000-y. Epub 2020 Feb, 12. PMID:32051583[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Suzuki H, Chiba T, Kobayashi M, Takeuchi M, Suzuki T, Ichiyama A, Ikenoue T, Omata M, Furuichi K, Tanaka K. IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2. Biochem Biophys Res Commun. 1999 Mar 5;256(1):127-32. PMID:10066435 doi:10.1006/bbrc.1999.0289
- ↑ Shirane M, Hatakeyama S, Hattori K, Nakayama K, Nakayama K. Common pathway for the ubiquitination of IkappaBalpha, IkappaBbeta, and IkappaBepsilon mediated by the F-box protein FWD1. J Biol Chem. 1999 Oct 1;274(40):28169-74. PMID:10497169
- ↑ Orian A, Gonen H, Bercovich B, Fajerman I, Eytan E, Israel A, Mercurio F, Iwai K, Schwartz AL, Ciechanover A. SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. EMBO J. 2000 Jun 1;19(11):2580-91. PMID:10835356 doi:10.1093/emboj/19.11.2580
- ↑ Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K. Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination. J Biol Chem. 2000 Jan 28;275(4):2877-84. PMID:10644755
- ↑ Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, Miyazono K. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol Biol Cell. 2001 May;12(5):1431-43. PMID:11359933
- ↑ Lassot I, Segeral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol. 2001 Mar;21(6):2192-202. PMID:11238952 doi:10.1128/MCB.21.6.2192-2202.2001
- ↑ Fong A, Sun SC. Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100. J Biol Chem. 2002 Jun 21;277(25):22111-4. Epub 2002 May 6. PMID:11994270 doi:10.1074/jbc.C200151200
- ↑ Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK. Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev Cell. 2003 Jun;4(6):813-26. PMID:12791267
- ↑ Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev. 2003 Dec 15;17(24):3062-74. Epub 2003 Dec 17. PMID:14681206 doi:10.1101/gad.1157503
- ↑ Mantovani F, Banks L. Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor. J Biol Chem. 2003 Oct 24;278(43):42477-86. Epub 2003 Aug 5. PMID:12902344 doi:http://dx.doi.org/10.1074/jbc.M302799200
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- ↑ Wan M, Tang Y, Tytler EM, Lu C, Jin B, Vickers SM, Yang L, Shi X, Cao X. Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. J Biol Chem. 2004 Apr 9;279(15):14484-7. Epub 2004 Feb 26. PMID:14988407 doi:10.1074/jbc.C400005200
- ↑ Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004 Oct;6(10):931-40. Epub 2004 Sep 26. PMID:15448698 doi:10.1038/ncb1173
- ↑ Wang B, Li Y. Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):33-8. Epub 2005 Dec 21. PMID:16371461 doi:10.1073/pnas.0509927103
- ↑ Baek K, Krist DT, Prabu JR, Hill S, Klugel M, Neumaier LM, von Gronau S, Kleiger G, Schulman BA. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature. 2020 Feb;578(7795):461-466. doi: 10.1038/s41586-020-2000-y. Epub 2020 Feb, 12. PMID:32051583 doi:http://dx.doi.org/10.1038/s41586-020-2000-y
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