The objective of the proposed studies is to use structural and biophysical methods to investigate the molecular mechanisms underlying the specific regulatory and targeting interactions of the Wnt signaling pathway. Wnt signaling plays an important role in embryonic development and in the regulation of cell growth. Inappropriate activation of Wnt signaling has been implicated in cancers and other human diseases. Dishevelled is an important player in the Wnt pathway. It relays the signal from the membrane-bound Wnt receptors to downstream partners. Sequence analysis revealed two new novel protein domains in Dishevelled: the DEP and DIX domains. It is believed that the DEP domain binds to the membrane-bound receptor and that the DIX domain interacts with downstream components. Protein NMR spectroscopy will be used to determine the structures of the two domains and the fundamental chemical nature of the interactions between both domains and their binding partners will be analyzed by structural and biophysical methods. Axin, one of the proteins downstream of Dishevelled, also contains a DIX domain. It has been hypothesized that the Wnt signal passes from Dishevelled to Axin through heterodimerization of the two DIX domains. This hypothesis will be examined by further analysis of the structures of the Axin DIX domain and the DIX heterodimer complex. The applicant suggests that these studies will reveal the first structural and functional information about DEP and DIX domains and, ultimately, may provide insights for the development of pharmaceutical agents that can interfere with specific Wnt signaling events in human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061739-03
Application #
6525933
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Flicker, Paula F
Project Start
2000-08-01
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
3
Fiscal Year
2002
Total Cost
$187,500
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Qi, Jing; Lee, Ho-Jin; Saquet, Audrey et al. (2017) Autoinhibition of Dishevelled protein regulated by its extreme C terminus plays a distinct role in Wnt/?-catenin and Wnt/planar cell polarity (PCP) signaling pathways. J Biol Chem 292:5898-5908
Shan, Jufang; Zhang, Xinxin; Bao, Ju et al. (2012) Synthesis of potent dishevelled PDZ domain inhibitors guided by virtual screening and NMR studies. Chem Biol Drug Des 79:376-83
Shan, Jufang; Zheng, Jie J (2009) Optimizing Dvl PDZ domain inhibitor by exploring chemical space. J Comput Aided Mol Des 23:37-47
Liu, Jing; Xing, Yi; Hinds, Thomas R et al. (2006) The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin. J Mol Biol 360:133-44
Dickerson, J Bradley; Morgan, Marc A; Mishra, Ashutosh et al. (2006) The influence of phosphorylation on the activity and structure of the neuronal IQ motif protein, PEP-19. Brain Res 1092:16-27
Shan, Jufang; Shi, De-Li; Wang, Junmei et al. (2005) Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44:15495-503
Gao, Yuan; Dickerson, J Bradley; Guo, Fukun et al. (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 101:7618-23
London, Timothy B C; Lee, Ho-Jin; Shao, Youming et al. (2004) Interaction between the internal motif KTXXXI of Idax and mDvl PDZ domain. Biochem Biophys Res Commun 322:326-32
Wong, Hing C; Liu, Gaohua; Zhang, Yong-Mei et al. (2002) The solution structure of acyl carrier protein from Mycobacterium tuberculosis. J Biol Chem 277:15874-80