HTLV-1 HBZ Protein Deregulates Interactions between Cellular Factors and the KIX Domain of p300/CBP

Cook, Pamela R.; Polakowski, Nicholas; Lemasson, Isabelle

doi:10.1016/j.jmb.2011.04.003

Cited by 37 publications

(60 citation statements)

References 66 publications

(137 reference statements)

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“…16 KIX also binds activation domains of several other mammalian transcription factors 10,13,37,38 and viral proteins [39][40][41] involved in the regulation of lymphopoiesis through their LXXLL sequence or more generic -x-x--sequence described by Lee et al, 10 which is typically preceding by an acidic residue (; Figure 5A). 6,11 Our PCET/KIX complex and associated mutagenesis studies described here provide structural insights into these functions.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1

Denis

Chitayat

Plevin

et al. 2012

Blood

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E-proteins are critical transcription factors in B-cell lymphopoiesis. E2A, 1 of 3 E-protein–encoding genes, is implicated in the induction of acute lymphoblastic leukemia through its involvement in the chromosomal translocation 1;19 and consequent expression of the E2A-PBX1 oncoprotein. An interaction involving a region within the N-terminal transcriptional activation domain of E2A-PBX1, termed the PCET motif, which has previously been implicated in E-protein silencing, and the KIX domain of the transcriptional coactivator CBP/p300, critical for leukemogenesis. However, the structural details of this interaction remain unknown. Here we report the structure of a 1:1 complex between PCET motif peptide and the KIX domain. Residues throughout the helical PCET motif that contact the KIX domain are important for both binding KIX and bone marrow immortalization by E2A-PBX1. These results provide molecular insights into E-protein–driven differentiation of B-cells and the mechanism of E-protein silencing, and reveal the PCET/KIX interaction as a therapeutic target for E2A-PBX1–induced leukemia.

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Section: Discussionmentioning

confidence: 99%

Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1

Denis

Chitayat

Plevin

et al. 2012

Blood

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“…A 45-μM solution of 15 N-labeled KIX L627C with or without conjugated small molecule was prepared in a 9:1 H 2 O:D 2 O 10-mM sodium phosphate buffer containing 100 mM NaCl, pH 7.2. HSQC experiments on 1 H- 15 N were recorded at 27°C on an Avance Bruker 600 MHz NMR spectrometer equipped with a 5-mm cryogenic probe. HSQC data were collected with the protein alone and the protein was covalently tethered to 1-10 and the chemical shifts were compared.…”

Section: Methodsmentioning

confidence: 99%

“…Conformational changes in both the TADs and KIX occur upon binding, and NMR solution studies have underscored that each TAD•KIX complex is conformationally unique (10,(12)(13)(14)25). However, the transient-state kinetic mechanism of two ligands binding cooperatively to the KIX domain has yet to be defined, and there is little information on the mechanism of how different protein ligands elicit differential degrees of allosteric effects (11,15). Answers to these questions are crucial for defining the communication pathways within CBP protein interaction networks.…”

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confidence: 99%

“…1A) (10). The interaction of a second ligand, phosphorylated kinase-inducible domain (pKID) of CREB, is enhanced (up to twofold) by the presence of MLL and several elegant studies have documented allosteric communication between the two binding sites (11)(12)(13)(14)(15). However, the relatively modest affinities (micromolar) of the native complexes and the aggregation propensities and the promiscuous binding profiles of the transcriptional activation domains have hampered kinetic dissection of this and other complexes (16,17).…”

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confidence: 99%

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Dissecting allosteric effects of activator–coactivator complexes using a covalent small molecule ligand

Wang

Lodge

Fierke³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Allosteric binding events play a critical role in the formation and stability of transcriptional activator-coactivator complexes, perhaps in part due to the often intrinsically disordered nature of one or more of the constituent partners. The kinase-inducible domain interacting (KIX) domain of the master coactivator CREB binding protein/ p300 is a conformationally dynamic domain that complexes with transcriptional activators at two discrete binding sites in allosteric communication. The complexation of KIX with the transcriptional activation domain of mixed-lineage leukemia protein leads to an enhancement of binding by the activation domain of CREB (phosphorylated kinase-inducible domain of CREB) to the second site. A transient kinetic analysis of the ternary complex formation aided by small molecule ligands that induce positive or negative cooperative binding reveals that positive cooperativity is largely governed by stabilization of the bound complex as indicated by a decrease in k off . Thus, this suggests the increased binding affinity for the second ligand is not due to an allosteric creation of a more favorable binding interface by the first ligand. This is consistent with data from us and from others indicating that the on rates of conformationally dynamic proteins approach the limits of diffusion. In contrast, negative cooperativity is manifested by alterations in both k on and k off , suggesting stabilization of the binary complex.IDP | protein-protein interaction P rotein-protein interactions (PPIs) underscore all cellular processes, and the mechanistic dissection of PPI networks is thus a high priority (1-4). A particular challenge is defining the mechanism of PPI formation between intrinsically disordered proteins (IDPs) where allosteric changes play a substantive role (5-7). Allosteric communication between binding sites is vital for the proper function of feedback and regulatory circuits in the cell (8, 9). For example, the conformationally dynamic kinase-inducible domain interacting (KIX) domain of the master transcriptional coactivator CREB binding protein (CBP) undergoes a structural shift and stabilization upon binding to a cognate ligand such as the intrinsically disordered transcriptional activation domain (TAD) of mixed-lineage leukemia protein (MLL) (Fig. 1A) (10). The interaction of a second ligand, phosphorylated kinase-inducible domain (pKID) of CREB, is enhanced (up to twofold) by the presence of MLL and several elegant studies have documented allosteric communication between the two binding sites (11-15). However, the relatively modest affinities (micromolar) of the native complexes and the aggregation propensities and the promiscuous binding profiles of the transcriptional activation domains have hampered kinetic dissection of this and other complexes (16,17).The coactivator CBP exists across metazoans (18)(19)(20) and is a transcription hub that interacts with numerous transcriptional activators, using several discrete domains (21,22). The KIX domain within CBP is a 90-residue motif ...

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“…All three proteins utilize intrinsically disordered interaction motifs to bind to the MLL site on the KIX domain (96 -98). Tax and HBZ compete with cellular transcription factors for binding to KIX, thereby interfering with CBP/p300-mediated transcriptional processes that regulate critical hematopoietic signaling pathways (98,99). Infection by these viruses is frequently a precursor to diseases such as leukemia.…”

Section: Viral Idps Compete With Cellular Proteins For Cbp/p300 Bindingmentioning

confidence: 99%

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

Dyson

Wright

2016

Journal of Biological Chemistry

274

270

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The transcriptional coactivators CREB-binding protein (CBP) and p300 undergo a particularly rich set of interactions with disordered and partly ordered partners, as a part of their ubiquitous role in facilitating transcription of genes. CBP and p300 contain a number of small structured domains that provide scaffolds for the interaction of disordered transactivation domains from a wide variety of partners, including p53, hypoxiainducible factor 1␣ (HIF-1␣), NF-B, and STAT proteins, and are the targets for the interactions of disordered viral proteins that compete with cellular factors to disrupt signaling and subvert the cell cycle. The functional diversity of the CBP/p300 interactome provides an excellent example of the power of intrinsic disorder to facilitate the complexity of living systems.

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HTLV-1 HBZ Protein Deregulates Interactions between Cellular Factors and the KIX Domain of p300/CBP

Cited by 37 publications

References 66 publications

Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1

Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1

Dissecting allosteric effects of activator–coactivator complexes using a covalent small molecule ligand

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

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