Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled.
The cytoplasmic protein Dishevelled (Dvl) and the associated membrane-bound receptor Frizzled (Fz) are essential in canonical and noncanonical Wnt signaling pathways. However, the molecular mechanisms underlying this signaling are not well understood. By using NMR spectroscopy, we determined that an internal sequence of Fz binds to the conventional peptide binding site in the PDZ domain of Dvl; this type of site typically binds to C-terminal binding motifs. The C-terminal region of the Dvl inhibitor Dapper (Dpr) and Frodo bound to the same site. In Xenopus, Dvl binding peptides of Fz and Dpr/Frodo inhibited canonical Wnt signaling and blocked Wnt-induced secondary axis formation in a dose-dependent manner, but did not block noncanonical Wnt signaling mediated by the DEP domain. Together, our results identify a missing molecular connection within the Wnt pathway. Differences in the binding affinity of the Dvl PDZ domain and its binding partners may be important in regulating signal transduction by Dvl.
Wong
Hing-C
HC
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Bourdelas
Audrey
A
Krauss
Anke
A
Lee
Ho-Jin
HJ
Shao
Youming
Y
Wu
Dianqing
D
Mlodzik
Marek
M
Shi
De-Li
DL
Zheng
Jie
J
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019521:Body Patterning; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051157:Frizzled Receptors; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008845:Microinjections; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D029961:Zebrafish Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C454443:DACT1 protein, Xenopus; C491683:DACT1 protein, human; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C093133:SIA1 protein, Xenopus; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C000606588:dsh protein, Drosophila; C058784:fz protein, Drosophila