RESUMO
The protein beta-catenin is an essential component of intercellular junctions and the Wnt growth factor signaling pathway. In many cancers, mutation of Wnt pathway components leads to activation of oncogenes by the beta-catenin-Tcf transcription factor complex. This complex is therefore an attractive target for anti-cancer drugs, but any such compound must selectively interfere with the beta-catenin-Tcf complex without disrupting other essential interactions of beta-catenin. Recent structural and biochemical studies have probed the molecular basis of ligand interaction by beta-catenin, and highlighted the possibilities and challenges of designing inhibitors of the beta-catenin-Tcf complex.
Assuntos
Caderinas/química , Caderinas/fisiologia , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/fisiologia , Desenho de Fármacos , Proteínas HMGB , Transativadores , Animais , Humanos , Junções Intercelulares/metabolismo , Modelos Moleculares , Estrutura Terciária de Proteína , Transdução de Sinais , Fatores de Transcrição TCF , Proteína 1 Semelhante ao Fator 7 de Transcrição , Fatores de Transcrição , beta CateninaRESUMO
The adenomatous polyposis coli (APC) tumor suppressor protein plays a critical role in regulating cellular levels of the oncogene product beta-catenin. APC binds to beta-catenin through a series of homologous 15 and 20 amino acid repeats. We have determined the crystal structure of a 15 amino acid beta-catenin binding repeat from APC bound to the armadillo repeat region of beta-catenin. Although it lacks significant sequence homology, the N-terminal half of the repeat binds in a manner similar to portions of E-cadherin and XTcf3, but the remaining interactions are unique to APC. We discuss the implications of this new structure for the design of therapeutics, and present evidence from structural, biochemical and sequence data, which suggest that the 20 amino acid repeats can adopt two modes of binding to beta-catenin.