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An intrinsically labile ?-helix abutting the BCL9-binding site of ?-catenin is required for its inhibition by carnosic acid.

ABSTRACT: Wnt/?-catenin signalling controls development and tissue homeostasis. Moreover, activated ?-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic ?-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of ?-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional ?-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile ?-helix (H1) amino-terminally abutting the BCL9-binding site in ?-catenin. Similarly, in colorectal cancer cells with hyperactive ?-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of ?-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of ?-catenin, which can be exploited for destabilization of oncogenic ?-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic ?-catenin.

SUBMITTER: de la Roche M

PROVIDER: S-EPMC3293410 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid.

de la Roche Marc M Rutherford Trevor J TJ Gupta Deepti D Veprintsev Dmitry B DB Saxty Barbara B Freund Stefan M SM Bienz Mariann M

Nature communications 20120221

Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from N ...[more]

PMID: 22353711

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Project description:We report a conformational switch between two distinct intrinsically disordered subensembles within the active site of a transcription factor. This switch highlights an evolutionary benefit conferred by the high plasticity of intrinsically disordered domains, namely, their potential to dynamically sample a heterogeneous conformational space housing multiple states with tailored properties. We focus on proto-oncogenic basic-helix-loop-helix (bHLH)-type transcription factors, as these play key roles in cell regulation and function. Despite intense research efforts, the understanding of structure-function relations of these transcription factors remains incomplete as they feature intrinsically disordered DNA-interaction domains that are difficult to characterize, theoretically as well as experimentally. Here we characterize the structural dynamics of the intrinsically disordered region DNA-binding site of the vital MYC-associated transcription factor X (MAX). Integrating nuclear magnetic resonance (NMR) measurements, molecular dynamics (MD) simulations, and electron paramagnetic resonance (EPR) measurements, we show that, in the absence of DNA, the binding site of the free MAX2 homodimer samples two intrinsically disordered conformational subensembles. These feature distinct structural properties: one subensemble consists of a set of highly flexible and spatially extended conformers, while the second features a set of "hinged" conformations. In this latter ensemble, the disordered N-terminal tails of MAX2 fold back along the dimer, forming transient long-range contacts with the HLH-region and thereby exposing the DNA binding site to the solvent. The features of these divergent substates suggest two mechanisms by which protein conformational dynamics in MAX2 might modulate DNA-complex formation: by enhanced initial recruitment of free DNA ligands, as a result of the wider conformational space sampled by the extended ensemble, and by direct exposure of the binding site and the corresponding strong electrostatic attractions presented while in the hinged conformations.

Dataset Information

An intrinsically labile ?-helix abutting the BCL9-binding site of ?-catenin is required for its inhibition by carnosic acid.

Publications

An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid.

Similar Datasets

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