32dh | pdb_000032dh
Crystal structure of YAP1(165-209) in complex with LATS2(511-522_C513S)
Structural highlights
FunctionYAP1_HUMAN Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical 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. Plays a key role to control cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage-independent growth, and epithelial mesenchymal transition (EMT) induction. Isoform 2 and isoform 3 can activate the C-terminal fragment (CTF) of ERBB4 (isoform 3).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe two paralogs YAP and TAZ act through TEAD transcription factors and bind PPxY motif proteins in the Hippo pathway via WW domains. YAP has up to two WW domains, whereas TAZ has one. Because YAP(WW1) and TAZ(WW) are the most similar in sequence, they can be considered as corresponding modules in these two proteins. This study shows that, despite their similarity, they differ strongly in conformational stability and in how they bind flexible ligands. Nano-differential scanning fluorimetry, circular dichroism, and NMR indicate that both isolated domains populate partially folded or exchanging states in solution, but TAZ(WW) is more thermally stable and has a larger folded population. Peptide binding stabilizes both domains, producing sharper NMR signals. Surface plasmon resonance measurements with PPxY peptides show micromolar affinities and generally modest differences between YAP(WW1) and TAZ(WW), although these differences increase for conformationally plastic ligands. A high resolution LATS2:YAP(WW1) crystal structure and molecular dynamics simulations suggest that preorganized peptides bind more tightly and less selectively, while flexible peptides incur larger binding penalties that dynamic YAP(WW1) compensates more effectively. These observations indicate that differences in WW-domain stability contribute to subtle YAP/TAZ binding preferences despite conserved binding surfaces and evolutionary relatedness between the paralogs. Comparing YAP(WW1) and TAZ(WW): Similar Binding Sites but Different Stability and Conformational Dynamics.,Merlen C, Mesrouze Y, Chau S, Diehl BA, Hinniger A, Zimmermann C, Meyerhofer M, Fontana P, Groebke S, Hinrichs J, Abdul Rahman W, Gutmann S, Fernandez C, Petrovic D, Chene P Biomolecules. 2026 Sep 17;16(9):1355. doi: 10.3390/biom16091355. PMID:42793187[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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