3rc0

Structural highlights

Function

[SETD6_HUMAN] Protein-lysine N-methyltransferase that specifically monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulate NF-kappa-B transcription factor activity.^[1] [TF65_HUMAN] NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1.^{[2] [3] [4] [5] [6] [7]}

See Also

• Histone methyltransferase 3D structures

References

1. ↑ Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O. Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. Nat Immunol. 2011 Jan;12(1):29-36. doi: 10.1038/ni.1968. Epub 2010 Dec 5. PMID:21131967 doi:10.1038/ni.1968
2. ↑ Schulte R, Grassl GA, Preger S, Fessele S, Jacobi CA, Schaller M, Nelson PJ, Autenrieth IB. Yersinia enterocolitica invasin protein triggers IL-8 production in epithelial cells via activation of Rel p65-p65 homodimers. FASEB J. 2000 Aug;14(11):1471-84. PMID:10928981
3. ↑ Asamitsu K, Tetsuka T, Kanazawa S, Okamoto T. RING finger protein AO7 supports NF-kappaB-mediated transcription by interacting with the transactivation domain of the p65 subunit. J Biol Chem. 2003 Jul 18;278(29):26879-87. Epub 2003 May 13. PMID:12748188 doi:10.1074/jbc.M211831200
4. ↑ Liu Y, Smith PW, Jones DR. Breast cancer metastasis suppressor 1 functions as a corepressor by enhancing histone deacetylase 1-mediated deacetylation of RelA/p65 and promoting apoptosis. Mol Cell Biol. 2006 Dec;26(23):8683-96. Epub 2006 Sep 25. PMID:17000776 doi:10.1128/MCB.00940-06
5. ↑ Sun S, Tang Y, Lou X, Zhu L, Yang K, Zhang B, Shi H, Wang C. UXT is a novel and essential cofactor in the NF-kappaB transcriptional enhanceosome. J Cell Biol. 2007 Jul 16;178(2):231-44. Epub 2007 Jul 9. PMID:17620405 doi:jcb.200611081
6. ↑ Ishaq M, Ma L, Wu X, Mu Y, Pan J, Hu J, Hu T, Fu Q, Guo D. The DEAD-box RNA helicase DDX1 interacts with RelA and enhances nuclear factor kappaB-mediated transcription. J Cell Biochem. 2009 Feb 1;106(2):296-305. doi: 10.1002/jcb.22004. PMID:19058135 doi:10.1002/jcb.22004
7. ↑ Sharif-Askari E, Vassen L, Kosan C, Khandanpour C, Gaudreau MC, Heyd F, Okayama T, Jin J, Rojas ME, Grimes HL, Zeng H, Moroy T. Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65. Mol Cell Biol. 2010 Aug;30(16):3929-42. doi: 10.1128/MCB.00087-10. Epub 2010 Jun , 14. PMID:20547752 doi:10.1128/MCB.00087-10
8. ↑ Chang Y, Levy D, Horton JR, Peng J, Zhang X, Gozani O, Cheng X. Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling. Nucleic Acids Res. 2011 Apr 22. PMID:21515635 doi:10.1093/nar/gkr256