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X-ray structure of TEAD4(E263A+Y429F mutant) complexed with YAP(wildtype): The role of residual flexibility and water molecules in the adaptation of a bound intrinsically disordered protein to mutations at a binding interfaceX-ray structure of TEAD4(E263A+Y429F mutant) complexed with YAP(wildtype): The role of residual flexibility and water molecules in the adaptation of a bound intrinsically disordered protein to mutations at a binding interface
Structural highlights
FunctionTEAD4_HUMAN Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved 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 MST1/MST2, 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. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif.[1] [2] Publication Abstract from PubMedMany 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 need a precise positioning of the interacting residues to be formed. We use as 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 key for the adaptation of IDPs to different interface landscapes and to mutations occurring at binding interfaces. This article is protected by copyright. All rights reserved. Adaptation of the bound intrinsically disordered protein YAP to mutations at the YAP:TEAD interface.,Mesrouze Y, Bokhovchuk F, Izaac A, Meyerhofer M, Zimmermann C, Fontana P, Schmelzle T, Erdmann D, Furet P, Kallen J, Chene P Protein Sci. 2018 Jul 29. doi: 10.1002/pro.3493. PMID:30058229[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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