Structures of YAP protein domains reveal promising targets for development of new cancer drugs

Abstract

YAP (Yes-associated protein) is a potent oncogene and a major effector of the mammalian Hippo tumor suppressor pathway. In this review, our emphasis is on the structural basis of how YAP recognizes its various cellular partners. In particular, we discuss the role of LATS kinase and AMOTL1 junction protein, two key cellular partners of YAP that bind to its WW domain, in mediating cytoplasmic localization of YAP and thereby playing a key role in the regulation of its transcriptional activity. Importantly, the crystal structure of an amino-terminal domain of YAP in complex with the carboxy-terminal domain of TEAD transcription factor was only recently solved at atomic resolution, while the structure of WW domain of YAP in complex with a peptide containing the PPxY motif has been available for more than a decade. We discuss how such structural information may be exploited for the rational development of novel anti-cancer therapeutics harboring greater efficacy coupled with low toxicity. We also embark on a brief discussion of how recent in silico studies led to identification of the cardiac glycoside digitoxin as a potential modulator of WW domain-ligand interactions. Conversely, dobutamine was identified in a screen of known drugs as a compound that promotes cytoplasmic localization of YAP, thereby resulting in growth suppressing activity. Finally, we discuss how a recent study on the dynamics of WW domain folding on a biologically critical time scale may provide a tool to generate repertoires of WW domain variants for regulation of the Hippo pathway toward desired, non-oncogenic outputs.

Figure 1

Modular structures of the two major isoforms of YAP protein. TEAD binding domain (bd), WW domains, SH3 domain-binding motif (bm) transcriptional activation domain (TAD), and PDZ domain-binding motif (bm) are demarcated on the scheme of structures. See text for more details.

Figure 2

In A is the ribbon structure of the amino-terminal region of YAP (in magenta) in complex with the carboxy-terminal region of TEAD transcription factor (matte gold). Note that YAP clips TEAD structure like a pair of forceps. In B, three major sites on TEAD (shown in green), which accommodate YAP, are demarcated in red. The first site binds α1 helix, the second side accommodates the linker sequence, and the third site binds the α2 helix. See text for more details. Both figures are a gift from Drs. Wan Jin Hong and Hai Wei Song (8). The permission to reproduce Figure 2B (from reference 8) was granted by the authors and the Cold Spring Harbor Laboratory Press.

Figure 3

Structural models of the WW domain of YAP in complex with PPxY peptides derived from LATS1 (a) and AMOTL1 (b). In each case, the β-strands in the WW domain are shown in yellow with loops depicted in gray and the ligand colored green. The side chain moieties of residues within WW domain engaged in key intermolecular contacts with the PPxY peptides are shown in red. The side chain moieties of counteracting residues within the peptides colored blue correspond to the PPxY motif. All structural models were built using the MODELLER software based on homology modeling [55]. For the structural models of WW domain of YAP1 in complex with PPxY peptides derived from LATS1 and AMOTL1, the NMR structure of WW domain of YAP1 bound to a peptide containing the PPxY motif was used as a template (PDB# 1JMQ). In each case, a total of 100 atomic models were calculated and the structure with the lowest energy, as judged by the MODELLER Objective Function, was selected for further analysis. The atomic models were rendered using RIBBONS [56].

Figure 4

Structural models of the WW domain of YAP in complex with digitoxin. For the model shown in the figure, the WW domain of dystrophin in complex with digitoxin was used as a template [10]. For more details see legend to Figure 3 and the text.