Structural Basis for Recognition of SMRT/N-CoR by the MYND Domain and Its Contribution to AML1/ETO's Activity

Liu, Yizhou; Chen, Wei; Gaudet, Justin; Cheney, Matthew D.; Roudaia, Liya; Cierpicki, Tomasz; Klet, Rachel C.; Hartman, Kari L.; Laue, Thomas M.; Speck, Nancy A.; Bushweller, John H.

doi:10.1016/j.ccr.2007.04.010

Cited by 104 publications

(149 citation statements)

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“…ZNF651 and ZNF652 carboxy-terminal proline-rich region conforms to this motif. MYND domains are defined by a C 4 -C 2 HC consensus and are frequently implicated in transcriptional repression [10,11]. Interaction of ZNF651 and ZNF652 with CBFA2T3 through their carboxy-terminal prolinerich conserved sequence further emphasises the functional significance of proline-rich regions in protein-protein interaction and cell signaling [12].…”

Section: Discussionmentioning

confidence: 99%

CBFA2T3–ZNF651, like CBFA2T3–ZNF652, functions as a transcriptional corepressor complex

et al. 2010

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a b s t r a c tA significant proportion of the human genome codes for transcription factors. Balanced activity of transcriptional activators and repressors is essential for normal development and differentiation. Previously we reported that a classical C 2 H 2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. It is suggested that CBFA2T3-ZNF651 and CBFA2T3-ZNF652 repressor complexes perform functionally similar roles in a tissue-specific manner. Structured summary:MINT-7555667: CBFA2T3 (uniprotkb:O75081) physically interacts (MI:0915) with ZNF651 (uniprotkb:Q9UFB7) by anti tag co-immunoprecipitation (MI:0007) Crown

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Section: Discussionmentioning

confidence: 99%

CBFA2T3–ZNF651, like CBFA2T3–ZNF652, functions as a transcriptional corepressor complex

et al. 2010

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Section: Nmr Spectroscopymentioning

confidence: 99%

“…For the stereospecific assignments of methyl groups of leucines and valines, 10% fractional 13 C-labeled eTAFH-HEB was prepared by growing cells in minimal media containing 90% 12 C-glucose and 10% 13 C-glucose. U-[ 15 N, 13 where ␦ i is the chemical shift at each titration point, L ti is the total ligand concentration at each titration point, P t is the total protein concentration, and ␦ b is the chemical shift of the fully bound form. 24,25 K d and ␦ b were determined by an iterative fitting routine.…”

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confidence: 99%

Structure of the AML1-ETO eTAFH domain–HEB peptide complex and its contribution to AML1-ETO activity

Park

Chen

Cierpicki

et al. 2009

Blood

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AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein-associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETOmediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO. IntroductionAML1-ETO is the fusion protein produced from the t(8;21) identified in acute myeloid leukemia (AML) of the M2 subtype. 1 The translocation fuses the N-terminus of RUNX1 with 575 amino acids of ETO ("eight twenty one," encoded by RUNX1T1). AML1-ETO has 5 conserved domains named for its Drosophila homologues Runt and Nervy: the DNA-and CBF␤-binding Runt domain from RUNX1, and Nervy homology domains 1 to 4 (NHR1-4) in ETO. 2-4 NHR1, also known (and referred to here) as the TATA box-binding protein-associated factor homology domain (eTAFH) is homologous to several TATA-binding protein associated factors (TAFs) and interacts with E proteins. 5 The NHR2 domain, or hydrophobic heptad repeat (HHR) is an ␣-helical tetramer that is essential for the activity of AML1-ETO. [6][7][8][9] NHR3 is a predominantly ␣-helical domain that interacts with the regulatory subunit of type II cyclic AMP-dependent protein kinase (PKA RII␣). 4 The NHR4 domain (also known as myeloid-Nervy-DEAF-1, or MYND) was suggested to contain 2 putative non-DNAbinding zinc-fingers. [10][11][12] We previously solved the structure of the MYND domain and showed it to be a member of the RING finger structural family. 13 The eTAFH domain is homologous to several TAFs, including Drosophila TAF110, human TAF130, and human TAF105. 3,14,15 Previous studies in a t(8;21) leukemic cell line showed that the eTAFH domain interacts with E proteins, 5 which are widely expressed DNA-binding transcription factors involved in regulating differentiation, proliferation, and apoptosis whose transactivation is facilitated by recruiting CBP/p300 histone acetyltransferases (HATs). [16][17][18] The eTAFH domain binds the AD1 transactivation domain of the HeLa cell E-boxbinding protein (HEB), an E protein family member, which prevents CBP/p300 and HAT association. This led to the hypothesis that AML1-ETO dominantly silences E proteins in t(8;21) cells, resulting in dysregulation of E protein target genes, and by that mechanism contributes to leukemogenesis. 5 Consistent with this, a recent chromatin immunoprecipitation (ChIP)-chip study shows eviden...

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“…51 We therefore tested whether the NHR2 domain-deletion mutant of AML1-ETO influences its DNA-binding affinity. The DNA-binding affinity assay with human separase TC probe revealed that wild-type AML1-ETO has a much higher binding affinity than the NHR2-deleted AML1-ETO ( Figure 3F lanes 3 and 4).…”

Section: Higher Dna-binding Affinity Of Aml1-eto For Double Aml1 Sitementioning

confidence: 99%

t(8;21)(q22;q22) fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression

Okumura

Peterson

Okumura

et al. 2008

Blood

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IntroductionThe t(8;21)(q22;q22) translocation is associated with nearly 40% of cases of the French-American-British (FAB) M2 subtype of acute myeloid leukemia (AML) and 8% to 20% of all cases of AML. [1][2][3][4] The AML1-ETO fusion protein generated due to this translocation contains the N-terminus of AML1 (also known as RUNX1, CBF␣2, PEBP2␣B) and almost full-length ETO (also known as MTG8). 5,6 The AML1 portion of AML1-ETO contains the Drosophila melanogaster protein Runt homology domain, which is essential for binding to DNA with its heterodimerization partner CBF␤, and lacks the C-terminal region required for transcriptional regulation. 7-13 AML1 modulates both growth and differentiation, and the analysis of Aml1 knockout mice demonstrates that AML1 is a crucial factor for definitive hematopoiesis. 14,15 In vitro studies showed that AML1 regulates the expression of growth factor receptors, cytokines, and enzymes involved in hematopoiesis. [16][17][18][19][20][21] More recently, AML1 was shown to have a role in the self-renewal potential and expansion of hematopoietic stem cells. [22][23][24] ETO contains 4 Nervy homology regions (NHR1-4) (reviewed by Peterson et al 25 ). NHR1 has sequence homology to TAF110 (TATA box binding protein-associated factor 110) and has been shown to associate with E proteins and Gfi-1. NHR2 contains a hydrophobic amino acid heptad repeat (HHR) and is critical for interactions with ETO family members (MTG8, MTG16, and MTGR1), oligomerization of AML1-ETO, and protein-protein interaction with proteins such as mSin3A, Gfi-1, BCL6, HDAC1, and HDAC3. NHR3 includes a predicted coiled-coil structure with a potential PKA-anchoring protein (AKAP) function. NHR4 also known as the myeloid-Nervy-DEAF1 (MYND) homology domain contains 2 zinc chelating centers and mediates protein-protein interactions with the corepressor complexes of nuclear receptor corepressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT). Targeted disruption of Eto revealed an important role in the gastrointestinal system. 26 The ETO portion of AML1-ETO was shown to recruit NCoR/SMRT-Sin3-histone deacetylase (HDAC) complexes, decreasing histone acetylation and chromatin accessibility at AML1 targets. [27][28][29] Various AML1 consensus DNA-binding sequences have been reported as PuACCPuCA (TG T / C GGT T / C ), 30 TTTGCGGTT A / T , 31 and PyGPyGGTPy ( T / C G C / T GGT T / C ). 32 Furthermore, PCR-based random sequence screening with purified bacterially expressed GST-tagged AML1a (aa's 1-250) determined the AML1 consensus DNA-binding sequence as TG T / C GGT. 7 Since AML1-ETO contains the AML1 DNA-binding domain, it is generally believed that AML1-ETO binds to the same DNA sequence as AML1.Previously, we reported that although full-length AML1-ETO is not leukemogenic in mice, a C-terminal truncated version of this fusion protein (AML1-ETOtr) is highly leukemogenic. 33 Moreover, we identified an alternatively spliced variant of AML1-ETO that includes ETO exon 9a and generates the fusion prot...

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Structural Basis for Recognition of SMRT/N-CoR by the MYND Domain and Its Contribution to AML1/ETO's Activity

Cited by 104 publications

References 56 publications

CBFA2T3–ZNF651, like CBFA2T3–ZNF652, functions as a transcriptional corepressor complex

CBFA2T3–ZNF651, like CBFA2T3–ZNF652, functions as a transcriptional corepressor complex

Structure of the AML1-ETO eTAFH domain–HEB peptide complex and its contribution to AML1-ETO activity

t(8;21)(q22;q22) fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression

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