5urn
From Proteopedia
NMR structure of the complex between the PH domain of the Tfb1 subunit from TFIIH and the transactivation domain 1 of p65
Structural highlights
Function[TFB1_YEAST] Acts as component of the general transcription and DNA repair factor IIH (TFIIH) core, which is essential for both basal and activated transcription, and is involved in nucleotide excision repair (NER) of damaged DNA. TFIIH has CTD kinase and DNA-dependent ATPase activity, and is essential for polymerase II transcription in vitro.[1] [2] [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.[3] [4] [5] [6] [7] [8] Publication Abstract from PubMedp65 is a member of the NF-kappaB family of transcriptional regulatory proteins that functions as the activating component of the p65-p50 heterodimer. Through its acidic transactivation domain (TAD), p65 has the capacity to form interactions with several different transcriptional regulatory proteins, including TFIIB, TFIIH, CREB-binding protein (CBP)/p300 and TAFII31. Like other acidic TADs, the p65 TAD contains two subdomains (p65TA1 and p65TA2) that interact with different regulatory factors depending on the target gene. Despite its role in controlling numerous NF-kappaB target genes, there are no high-resolution structures of p65TA1 bound to a target transcriptional regulatory factor. In this work, we characterize the interaction of p65TA1 with two factors, the Tfb1/p62 subunit of TFIIH and the KIX domain of CBP. In these complexes, p65TA1 transitions into a helical conformation that includes its characteristic PhiXXPhiPhi motif (Phi = hydrophobic amino acid). Structural and functional studies demonstrate that the two binding interfaces are primarily stabilized by three hydrophobic amino acids within the PhiXXPhiPhi motif and these residues are also crucial to its ability to activate transcription. Taken together, the results provide an atomic level description of how p65TA1 is able to bind different transcriptional regulatory factors needed to activate NF-kappaB target genes. Structural characterization of interactions between transactivation domain 1 of the p65 subunit of NF-kappaB and transcription regulatory factors.,Lecoq L, Raiola L, Chabot PR, Cyr N, Arseneault G, Legault P, Omichinski JG Nucleic Acids Res. 2017 Feb 28. doi: 10.1093/nar/gkx146. PMID:28334776[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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