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Structural insights into the YAP and TEAD complex.

ABSTRACT: The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86-100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP-TEAD interaction, and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases.

SUBMITTER: Li Z

PROVIDER: S-EPMC2811825 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Structural insights into the YAP and TEAD complex.

Li Ze Z Zhao Bin B Wang Ping P Chen Fei F Dong Zhenghong Z Yang Huirong H Guan Kun-Liang KL Xu Yanhui Y

Genes & development 20100201 3

The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserv ...[more]

PMID: 20123905

Similar Datasets

Crystal structure of TAZ-TEAD complex reveals a distinct interaction mode from that of YAP-TEAD complex.

Project description:The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure. The second is a unique binding mode, whereby two molecules of TAZ bind to and bridge two molecules of TEAD4. We validated the latter using cross-linking and multi-angle light scattering. Using siRNA, we showed that TAZ knockdown leads to a decrease in TEAD4 dimerization. Lastly, results from luciferase assays, using YAP/TAZ transfected or knockdown cells, give support to the non-redundancy of YAP/TAZ co-activators in regulating gene expression in the Hippo pathway.

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Project description:The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.

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New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer.

Project description:The Hippo pathway is conserved across species. Key mammalian Hippo pathway kinases, including MST1/2 and LATS1/2, inhibit cellular growth by inactivating the TEAD coactivators, YAP, and TAZ. Extensive research has illuminated the roles of Hippo signaling in cancer, development, and regeneration. Notably, dysregulation of Hippo pathway components not only contributes to tumor growth and metastasis, but also renders tumors resistant to therapies. This review delves into recent research on YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ's biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.

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Repurposing of Drugs Targeting YAP-TEAD Functions.

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MRTF potentiates TEAD-YAP transcriptional activity causing metastasis.

Project description:Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical extracellular cues. The mechanism underlying this crosstalk, however, remains unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD-YAP transcriptional complex and potentiate its transcriptional activity. We show this interaction of MRTF and YAP is critical for LPA-induced cancer cell invasion in vitro and breast cancer metastasis to the lung in vivo We also demonstrate the significance of MRTF-YAP binding in regulation of YAP activity upon acute actin cytoskeletal damage. Acute actin disruption induces nucleo-cytoplasmic shuttling of MRTF, and this process underlies the LATS-independent regulation of YAP activity. Our results provide clear evidence of crosstalk between MRTF and YAP independent of the LATS kinases that normally act upstream of YAP signaling. Our results also suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP.

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Toward the Discovery of a Novel Class of YAP?TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP?TEAD Protein?Protein Interface.

Project description:Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP50?71-hTEAD1209?426 complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD. Four different chemical families have been identified and evaluated using biophysical techniques (thermal shift assay, microscale thermophoresis) and in cellulo assays (luciferase activity in transfected HEK293 cells, RTqPCR in MDA-MB231 cells). A first promising hit with micromolar inhibition in the luciferase gene reporter assay was discovered. This hit also decreased mRNA levels of TEAD target genes.

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Identification of Celastrol as a Novel YAP-TEAD Inhibitor for Cancer Therapy by High Throughput Screening with Ultrasensitive YAP/TAZ-TEAD Biosensors.

Project description:The Hippo pathway has emerged as a key signaling pathway that regulates a broad range of biological functions, and dysregulation of the Hippo pathway is a feature of a variety of cancers. Given this, some have suggested that disrupting the interaction of the Hippo core component YAP and its paralog TAZ with transcriptional factor TEAD may be an effective strategy for cancer therapy. However, there are currently no clinically available drugs targeting the YAP/TAZ-TEAD interaction for cancer treatment. To facilitate screens for small molecule compounds that disrupt the YAP-TEAD interaction, we have developed the first ultra-bright NanoLuc biosensor to quantify YAP/TAZ-TEAD protein-protein interaction (PPI) both in living cells and also in vitro using biosensor fusion proteins purified from bacteria. Using this biosensor, we have performed an in vitro high throughput screen (HTS) of small molecule compounds and have identified and validated the drug Celastrol as a novel inhibitor of YAP/TAZ-TEAD interaction. We have also demonstrated that Celastrol can inhibit cancer cell proliferation, transformation, and cell migration. In this study, we describe a new inhibitor of the YAP/TAZ-TEAD interaction warranting further investigation and offer a novel biosensor tool for the discovery of other new Hippo-targeting drugs in future work.

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Project description:Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ-TEAD transcriptional complex. Here, we uncover a context-dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD-mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR-TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of MST1/2 or LATS1/2, or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants.

| S-SCDT-10_15252-EMBJ_2022112184 | biostudies-other

Adaptation of the bound intrinsically disordered protein YAP to mutations at the YAP:TEAD interface.

Project description:Many interactions between proteins are mediated by intrinsically disordered regions (IDRs). Intrinsically disordered proteins (IDPs) do not adopt a stable three-dimensional structure in their unbound form, but they become more structured upon binding to their partners. In this communication, we study how a bound IDR adapts to mutations, preventing the formation of hydrogen bonds at the binding interface that needs a precise positioning of the interacting residues to be formed. We use as a model the YAP:TEAD interface, where one YAP (IDP) and two TEAD residues form hydrogen bonds via their side chain. Our study shows that the conformational flexibility of bound YAP and the reorganization of water molecules at the interface help to reduce the energetic constraints created by the loss of H-bonds at the interface. The residual flexibility/dynamic of bound IDRs and water might, therefore, be a key for the adaptation of IDPs to different interface landscapes and to mutations occurring at binding interfaces.

| S-EPMC6199158 | biostudies-literature

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