The paralogous multi-functional adaptor proteins YAP and TAZ are nuclear effectors of
the Hippo pathway, a central regulator of developmental organ size control, tissue
homeostasis and tumour suppression. YAP/TAZ target the TEAD transcription factor
family to promote cell survival and inhibit apoptosis. TEAD proteins contain a DNAbinding
domain and a YAP/TAZ interaction domain. PCR analysis of medaka fish
TEAD cDNA revealed the presence of alternative TEAD splice-forms with variations at
the C-terminus of the DNA-binding domain. Structural analysis indicated the YAPbinding
domain of TEAD proteins is folded and globular. NMR spectroscopy showed
that the TEAD binding domain of YAP does not contain secondary structure. YAP and
TAZ both contain WW domains, which are small protein-protein interaction modules.
Two YAP isoforms are known, YAP1 and YAP2 that contain one and two WW
domains, respectively. To date, only a single WW isoform of TAZ has been described.
PCR analysis of medaka TAZ cDNA identified both single WW and tandem WW
isoforms of TAZ. NMR spectroscopy was used to characterise structural,
conformational, and peptide binding features of the tandem WW domains from YAP
and TAZ. The YAP WW2 solution structure confirms that the domain has the canonical
anti-parallel β-sheet WW fold. WW1 of YAP and both WW domains of TAZ undergo
conformational exchange. The region linking the two WW domains is flexible and
allows interaction of both WW domains with peptides containing single and dual PPxY
binding motifs. In addition to YAP and TAZ, tandem WW domains are also present in
the core and upstream Hippo pathway proteins Salvador and Kibra. Both proteins
contain one atypical WW domain; the tandem WW domains of these two proteins are
unstable. Understanding structure and function of Hippo pathway components could
contribute to drug development and will also contribute to knowledge of protein folding
and interactions.
- Kibra
- Salvador
- YAP
- WW domains
- TAZ
- TEAD
- protein structure
- Hippo pathway
- NMR
- x-ray crystallography
Structural and functional studies of proteins from the Hippo signalling pathway
Cherrett, C. (Author). 1 Sept 2011
Student thesis: Doctoral Thesis › PhD