| Structural highlights
Disease
[WWTR1_HUMAN] Epithelioid hemangioendothelioma.
Function
[1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. [WWTR1_HUMAN] Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. Regulates the nuclear accumulation of SMADS and has a key role in coupling them to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition.[1] [2] [3] [4]
Publication Abstract from PubMed
Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This x-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.
Fragment-based Differential Targeting of PPI Stabilizer Interfaces.,Guillory X, Wolter M, Leysen S, Neves JF, Kuusk A, Genet S, Somsen B, Morrow J, Rivers E, van Beek L, Patel J, Goodnow R, Schoenherr H, Fuller N, Cao Q, Doveston RG, Brunsveld L, Arkin MR, Castaldi MP, Boyd H, Landrieu I, Chen H, Ottmann C J Med Chem. 2020 Jun 5. doi: 10.1021/acs.jmedchem.9b01942. PMID:32501690[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 2000 Dec 15;19(24):6778-91. PMID:11118213 doi:http://dx.doi.org/10.1093/emboj/19.24.6778
- ↑ Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008 Apr;28(7):2426-36. doi: 10.1128/MCB.01874-07. Epub 2008 Jan, 28. PMID:18227151 doi:http://dx.doi.org/10.1128/MCB.01874-07
- ↑ Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol. 2008 Jul;10(7):837-48. doi: 10.1038/ncb1748. Epub 2008 Jun 22. PMID:18568018 doi:http://dx.doi.org/10.1038/ncb1748
- ↑ Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Cristofaro T, Del Prete D, Pappalardo A, Mascia A, Zannini M. TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation. Exp Cell Res. 2009 Jan 15;315(2):162-75. doi: 10.1016/j.yexcr.2008.10.016. Epub, 2008 Oct 28. PMID:19010321 doi:http://dx.doi.org/10.1016/j.yexcr.2008.10.016
- ↑ Guillory X, Wolter M, Leysen S, Neves JF, Kuusk A, Genet S, Somsen B, Morrow J, Rivers E, van Beek L, Patel J, Goodnow R, Schoenherr H, Fuller N, Cao Q, Doveston RG, Brunsveld L, Arkin MR, Castaldi MP, Boyd H, Landrieu I, Chen H, Ottmann C. Fragment-based Differential Targeting of PPI Stabilizer Interfaces. J Med Chem. 2020 Jun 5. doi: 10.1021/acs.jmedchem.9b01942. PMID:32501690 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01942
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