Cryptic inhibitory regions nearby activation domains

Knight, Andrea; Piskáček, Martin

doi:10.1016/j.biochi.2022.05.004

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Previously, we had identified the nine-amino-acid activation domains (9aaTAD) using our prediction algorithm (www.med.muni.cz/9aaTAD) in numerous transcription factors including members of the Gal4-p53-E2A-MLL-SREBP-NF-SP-KLF-SOX families [31][32][33][34][35][36][37][38][39]. Recently, we have identified the 9aaTAD activation domain in MYCN and also in all Yamanaka transcription activators and showed the 9aaTADs activating transcription as short peptides [40].…”

Section: Introductionmentioning

confidence: 99%

Undruggable oncoproteins cMyc and NMyc bind to mediator of transcription with superior high affinity

Knight,

Houser,

Otasevic

et al. 2024

Preprint

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The overexpression of MYC genes is frequently found in many human cancers including adult and pediatric malignant brain tumors. Targeting MYC genes continues to be challenging due to their undruggable nature. The nine-amino-acid activation domain (9aaTAD) has been identified using our prediction algorithm in all four Yamanaka factors including c-Myc and showed to activate transcription as short peptides. We generated a set of c-Myc constructs (1-108, 69-108 and 98-108) in the N-terminal regions and tested their ability to initiate transcription. We discovered strong interactions in nanomolar scale between the 9aaTAD of c-Myc and N-Myc proteins with the KIX domain of CBP coactivator. The c-Myc 9aaTAD (region 98-108) was not overlapping with the MBII (region 128-143) and therefore represents TRRAP independent activation region. Next, we showed the 9aaTADs in human c-Myc and N-Myc conservation within the MYC family. Interestingly, the loss of the 9aaTAD in L-Myc paralogs was identified in higher metazoans suggesting the deletions had occurred in early tetrapod evolution. In summary, as c-Myc is largely intrinsically disordered protein and therefore difficult to target by small molecule inhibitors, our finding of the c-Myc 9aaTAD in complex with the KIX domain represents a promising druggable target for development of new peptide inhibitors in MYC-driven tumors.

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Section: Introductionmentioning

confidence: 99%

Undruggable oncoproteins cMyc and NMyc bind to mediator of transcription with superior high affinity

Knight,

Houser,

Otasevic

et al. 2024

Preprint

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“…The 9aaTAD family is represented by well-studied transcription factors Gal4, p53, MLL, E2A and SREBP1. The 9aaTADs were found in the SP and KLF family (Sp1-9, Klf1, KLF2, Klf3, Klf4, Klf5, Klf6, Klf7, Klf8, Klf12, Klf15, WT1) [6], SOX family (Sox1, Sox2, Sox3, Sox4, Sox7, Sox8, Sox9, Sox10, Sox11, Sox17, Sox18) [7,9,10], nuclear hormone receptors (RARa, HNF4, PPAR, VDR, NHR49) [5], SREBP family (SREBP1, SREBP2) [6], p53 family [3], TCF family (TCF3/E2A, TCF4, TCF12/HEB, CEBPB, CEBPA, CEBPD, CEBPE) [1,8], NF family (NFIA, NFIB, NFIC, NFIX), MYC family (c-myc, N-Myc, L-Myc) [7], in yeast transcription factors (Gal4, Oaf1, Pip2, Pdr1, Pdr3, Rtg3, Gln3, Gcn4, Pho4, Msn2, Msn4, Met4) [4,10,11], and also in artificial activators of transcription (P201, B42, p53-ECapLL, KBP 2.20, pRJR200, G80BP-A, G80BP-B) [3,11]. The curated 9aaTADs have been annotated on the protein database UniProt (https://www.uniprot.org/uniprot/?query=9aatad&sort=score).…”

Section: Introductionmentioning

confidence: 99%

The NFkB activation domain is 14-amino-acid-long variant of the 9aaTAD

Houser

Jendruchova

Knight

et al. 2023

Biochemical Journal

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The nine-amino-acid TransActivation Domains (9aaTAD) was identified in numerous transcription factors including Gal4, p53, E2A, MLL, c-Myc, N-Myc, and also in SP, KLF and SOX families. Most of the 9aaTAD domains interact with the KIX domain of transcription mediators MED15 and CBP to activate transcription. The NFkB activation domain occupied the same position on the KIX domain as the 9aaTADs of MLL, E2A and p53. Binding of the KIX domain is established by the two-point interaction involving 9aaTAD positions p3-4 and p6-7. The NFkB primary binding region (position p3-4) is almost identical to MLL and E2A, but secondary NFkB binding region differs by the position and engages the distal NFkB region p10-11. Thus, the NFkB activation domain is 5 amino acids longer than the other 9aaTADs. The NFkB activation domain includes an additional region, which we called the Omichinski Insert extending activation domain length to 14 amino acids. By deletion, we demonstrated that Omichinski Insert is an entirely non-essential part of NFkB activation domain. In summary, we recognized the NFkB activation domain as prolonged 9aaTAD conserved in evolution from humans to amphibians.

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Functional Characterization of Tea Plant (Camellia sinensis L.) CsCBF2 Gene Involved in Multiple Abiotic Stress Response in Tobacco (Nicotiana tabacum L.)

et al. 2022

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C-repeat binding factors/dehydration responsive element binding factors 1 (CBFs/DREB1s) are a small family of transcription factors that play important roles in plant resistance to various external stresses. However, functional characterization of tea plant (Camellia sinensis L.) CBF gene (CsCBF) was still seldom reported. Here, functional study of the cold-responsive CBF gene (CsCBF2) was done. Results showed that CsCBF2 had conserved AP2 DNA-binding domain and the typical PKK/RPAGRxKFxETRHP and DSAWR signature sequences of CBF/DREB1. Yeast one-hybrid and transcription activation assays revealed that the activation domain of CsCBF2 could activate the reporter gene expression, and the N terminal of CsCBF2 displayed an inhibitory effect. Although CsCBF2 was conserved to bind the C-repeat/dehydration-responsive element (CRT/DRE), intact CsCBF2 protein preferred the CRT cis element. Under normal growth conditions, CsCBF2-overexpressing tobacco plants (CsCBF2-OX) exhibited lighter green leaf color, growth retardation, and dwarfism. Smaller leaf of CsCBF2-OX was only seen in eight weeks after been sown in soil. Under cold, salinity, or drought stress, CsCBF2-OX displayed better growing with longer roots, heavier fresh weight, higher germination rate, and accumulated more proline and sugar contents, but lower electrolyte leakage. The results demonstrated that CsCBF2 enhanced plant tolerance to multiple abiotic stresses.

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Cryptic inhibitory regions nearby activation domains

Cited by 3 publications

References 24 publications

Undruggable oncoproteins cMyc and NMyc bind to mediator of transcription with superior high affinity

Undruggable oncoproteins cMyc and NMyc bind to mediator of transcription with superior high affinity

The NFkB activation domain is 14-amino-acid-long variant of the 9aaTAD

Functional Characterization of Tea Plant (Camellia sinensis L.) CsCBF2 Gene Involved in Multiple Abiotic Stress Response in Tobacco (Nicotiana tabacum L.)

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