The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček, Martin; Havelka, Marek; Jendruchova, Kristina; Knight, Andrea; Keegan, Liam P.

doi:10.1007/s00018-019-03251-w

Cited by 10 publications

(16 citation statements)

References 89 publications

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“…Contrary, the exclusively hydrophobic residues as are V, I, and A could be unfavorable for positions p3, p4 and p6, p7. 46 From that, none of the simplified hydrophobic residues (Φ = A, L, I, V, F) patterns as are ΦxxΦΦ and ΦΦxxΦ, proposed by others, could fit the 9aaTAD family pattern derived from Gal4, Oaf1, Pdr1, Msn2, E2A, and large activators families p53, SP, KLF, SOX. 2,[4][5][6]47,48 Regardless of the 9aaTAD sequence heterogeneity, the KIX enhanced folding could be observed in the KIX complexes with MLL, MLL mutants, p53, and p53hybrids, E2A, MAML2, and NFkB.…”

Section: Simplified Hydrophobic Residues Patterns φXxφφ and φφXxφ For Kix Bindingmentioning

confidence: 94%

Universal two‐point interaction of mediator KIX with 9aaTAD activation domains

Hofrova

Louša

Kubíčková

et al. 2021

J of Cellular Biochemistry

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The nine-amino-acid activation domain (9aaTAD) is defined by a short amino acid pattern including two hydrophobic regions (positions p3-4 and p6-7). The KIX domain of mediator transcription CBP interacts with the 9aaTAD domains of transcription factors MLL, E2A, NF-kB, and p53. In this study, we analyzed the 9aaTADs-KIX interactions by nuclear magnetic resonance. The positions of three KIX helixes α1-α2-α3 are influenced by sterically-associated hydrophobic I611, L628, and I660 residues that are exposed to solvent. The positions of two rigid KIX helixes α1 and α2 generate conditions for structural folding in the flexible KIX-L12-G2 regions localized between them. The three KIX I611, L628, and I660 residues interact with two 9aaTAD hydrophobic residues in positions p3 and p4 and together build a hydrophobic core of five residues (5R). Numerous residues in 9aaTAD position p3 and p4 could provide this interaction. Following binding of the 9aaTAD to KIX, the hydrophobic I611, L628, and I660 residues are no longer exposed to solvent and their position changes inside the hydrophobic core together with position of KIX α1-α2-α3 helixes. The new positions of the KIX helixes α1 and α2 allow the KIX-L12-G2 enhanced formation. The second hydrophobic region of the 9aaTAD (positions p6 and p7) provides strong binding with the KIX-L12-G2 region. Similarly, multiple residues in 9aaTAD position p6 and p7 could provide this interaction. In conclusion, both 9aaTAD regions p3, p4 and p6, p7 provide co-operative and highly universal binding to mediator KIX. The hydrophobic core 5R formation allows new positions of the rigid KIX α-helixes and enables the enhanced formation of the KIX-L12-G2 region. This contributes to free energy and is the key for the KIX-9aaTAD binding. Therefore, the 9aaTAD-KIX interactions do not operate under the rigid key-and-lock mechanism what explains the 9aaTAD natural variability.

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Section: Simplified Hydrophobic Residues Patterns φXxφφ and φφXxφ For Kix Bindingmentioning

confidence: 94%

Universal two‐point interaction of mediator KIX with 9aaTAD activation domains

Hofrova

Louša

Kubíčková

et al. 2021

J of Cellular Biochemistry

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“…transcription factors were linked with their full or partial inhibition, which corresponds well to lower activities of mbr and aqu Myc constructs in our transactivation assay (22).…”

Section: Previously the Accumulations Of Valines And Isoleucines In mentioning

confidence: 64%

“…and E2A (SDIM D FVLK -SDLL D FSAM) or human Myc and rat p53 (EMVT E LLGG -QDVA E LLEG) or human / Crassostrea gigas KLF4 and Oaf2 (LLDL D FIL / LLDY D FIL -LFDY D FLF)(14,22). All that supports that 9aaTAD domains have a natural prevalence for some variants despite their tentatively huge variability.In our study, we have identified activation domains in all four Yamanaka factors, Oct4,Sox2, Myc, and Klf4.…”

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confidence: 79%

“…The Gal4 activation domain (DDVY N YLFD) is conserved only in the 9aaTAD region especially in ancestral orthologs as are Hansenula fabianii or Wickerhamomyces ciferrii, whose activation domain is hardly acidic (NDFY S LIFN) (24). Moreover, we recently demonstrated that the exchange of all negatively charged residues for positively charged ones and vice versa in Gal4 and respectively in Sp1 activation domains did not interfere with their function as strong activators of transcription (22).…”

Section: Introductionmentioning

confidence: 98%

“…in p53. Accumulation of valines or isoleucines can compromise or fully inactivate the 9aaTAD function (22).…”

Section: Introductionmentioning

confidence: 99%

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The 9aaTAD activation domains in the four Yamanaka Oct4, Sox2, Myc, and Klf4 transcription factors essential during the stem cell development

Piskáček

Jendruchova

Řezáčová

et al. 2019

Preprint

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Somatic cells can be reprogrammed by the Yamanaka factors Oct4, Sox2, Myc and Klf4 activators into induced pluripotent stem cells. Throughout their genome, the Oct4, Sox2 and Klf4 cooperate with mediators of transcription, where the DNA binding sites serve as scaffolds for the phase-separated transcriptional condensates at distinct genome loci. In this study, we identified the 9aaTAD activation domains as the common interaction interface of the Yamanaka factors for transcription machinery. All four activation domains were identified by our online 9aaTAD prediction service and experimentally confirmed as strong activators of transcription.We considered the mediator interactions granted by 9aaTADs as part of the Yamanaka factors ability to reprogram cell fate.

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