| Structural highlights
Disease
CUL4B_HUMAN Defects in CUL4B are the cause of mental retardation, X-linked, syndromic, 15 (MRXS15) [MIM:300354. A syndromic form of X-linked mental retardation characterized by severe intellectual deficit associated with short stature, craniofacial dysmorphism, small testes, muscle wasting in lower legs, kyphosis, joint hyperextensibility, pes cavus, small feet, and abnormalities of the toes. Additional neurologic manifestations include speech delay and impairment, tremor, seizures, gait ataxia, hyperactivity and decreased attention span.[1] [2] [3] [4]
Function
CUL4B_HUMAN Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition subunit. CUL4B may act within the complex as a scaffold protein, contributing to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. Plays a role as part of the E3 ubiquitin-protein ligase complex in polyubiquitination of CDT1, histone H2A, histone H3 and histone H4 in response to radiation-induced DNA damage. Targeted to UV damaged chromatin by DDB2 and may be important for DNA repair and DNA replication. Required for ubiquitination of cyclin E, and consequently, normal G1 cell cycle progression. Regulates the mammalian target-of-rapamycin (mTOR) pathway involved in control of cell growth, size and metabolism. Specific CUL4B regulation of the mTORC1-mediated pathway is dependent upon 26S proteasome function and requires interaction between CUL4B and MLST8.[5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Molecules that induce novel interactions between proteins hold great promise for the study of biological systems and the development of therapeutics, but their discovery has been limited by the complexities of rationally designing interactions between three components, and because known binders to each protein are typically required to inform initial designs. Here, we report a general and rapid method for discovering alpha-helically constrained (Helicon) polypeptides that cooperatively induce the interaction between two target proteins without relying on previously known binders or an intrinsic affinity between the proteins. We show that Helicons are capable of binding every major class of E3 ubiquitin ligases, which are of great biological and therapeutic interest but remain largely intractable to targeting by small molecules. We then describe a phage-based screening method for discovering "trimerizer" Helicons, and apply it to reprogram E3s to cooperatively bind an enzyme (PPIA), a transcription factor (TEAD4), and a transcriptional coactivator (beta-catenin).
Recognition and reprogramming of E3 ubiquitin ligase surfaces by alpha-helical peptides.,Tokareva OS, Li K, Travaline TL, Thomson TM, Swiecicki JM, Moussa M, Ramirez JD, Litchman S, Verdine GL, McGee JH Nat Commun. 2023 Nov 1;14(1):6992. doi: 10.1038/s41467-023-42395-z. PMID:37914719[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am J Hum Genet. 2007 Mar;80(3):561-6. Epub 2007 Jan 25. PMID:17273978 doi:10.1086/512489
- ↑ Badura-Stronka M, Jamsheer A, Materna-Kiryluk A, Sowinska A, Kiryluk K, Budny B, Latos-Bielenska A. A novel nonsense mutation in CUL4B gene in three brothers with X-linked mental retardation syndrome. Clin Genet. 2010 Feb;77(2):141-4. doi: 10.1111/j.1399-0004.2009.01331.x. Epub, 2009 Dec 10. PMID:20002452 doi:10.1111/j.1399-0004.2009.01331.x
- ↑ Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet. 2007 Feb;80(2):345-52. Epub 2007 Jan 4. PMID:17236139 doi:10.1086/511134
- ↑ Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, Stratton MR. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet. 2009 May;41(5):535-43. doi: 10.1038/ng.367. Epub 2009 Apr 19. PMID:19377476 doi:10.1038/ng.367
- ↑ Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H. Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. Nat Cell Biol. 2003 Nov;5(11):1008-15. Epub 2003 Oct 26. PMID:14578910 doi:10.1038/ncb1061
- ↑ Higa LA, Yang X, Zheng J, Banks D, Wu M, Ghosh P, Sun H, Zhang H. Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation. Cell Cycle. 2006 Jan;5(1):71-7. Epub 2006 Jan 21. PMID:16322693
- ↑ Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell. 2006 May 5;22(3):383-94. PMID:16678110 doi:S1097-2765(06)00230-9
- ↑ Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapic-Otrin V. The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A. Cancer Res. 2008 Jul 1;68(13):5014-22. PMID:18593899 doi:68/13/5014
- ↑ Ghosh P, Wu M, Zhang H, Sun H. mTORC1 signaling requires proteasomal function and the involvement of CUL4-DDB1 ubiquitin E3 ligase. Cell Cycle. 2008 Feb 1;7(3):373-81. Epub 2007 Nov 2. PMID:18235224
- ↑ Zou Y, Mi J, Cui J, Lu D, Zhang X, Guo C, Gao G, Liu Q, Chen B, Shao C, Gong Y. Characterization of nuclear localization signal in the N terminus of CUL4B and its essential role in cyclin E degradation and cell cycle progression. J Biol Chem. 2009 Nov 27;284(48):33320-32. doi: 10.1074/jbc.M109.050427. Epub, 2009 Oct 2. PMID:19801544 doi:10.1074/jbc.M109.050427
- ↑ Tokareva OS, Li K, Travaline TL, Thomson TM, Swiecicki JM, Moussa M, Ramirez JD, Litchman S, Verdine GL, McGee JH. Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides. Nat Commun. 2023 Nov 1;14(1):6992. PMID:37914719 doi:10.1038/s41467-023-42395-z
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