Structure and Function of Wnt Signaling Protein Dishevelled

The relationship between amino acid sequence, tertiary structure and biological function of proteins is one of the most intensely pursued areas in molecular biology and biochemistry. A full understanding of how a biologic macromolecule functions is not possible until its three- dimensional structure has been determined at molecular level. Two techniques, X-ray crystallography and nuclear magnetic resonance (NMR), are currently popular for such task. Being a relatively new technique, NMR has made it possible to elucidate the protein structures in a solution environment that is much closer to the natural situation in a living being than the single crystals required for protein crystallography.

I will try to explain how the structure is determined by NMR with emphasis on how we calculate the structures based on the geometric conformational restraints derived from NMR data. The DEP domain of protein Dishevelled, a protein that the structure has just been solved in our lab, will be used as an example in the discussion. Dishevelled is an important player in the Wnt signal transduction 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 relays the signal from the membrane-bound Wnt receptors to the downstream partners. Sequence analysis revealed a novel protein domain, the DEP domain. Our structural studies shed the light on the function of this protein.

Inspired by the impact of the genome sequencing projects, researchers in structural biology realize that a crucial step in understanding living systems, following the completion of the sequence of the human genome, is the determination of the structure and function of the entire set of gene products. The needed of the determination of a large number of protein structures in a high throughput mode is indisputable. Since the structural calculation is the essential step in the protein NMR structural studies, and the large-scale calculation a key factor, we hope that new technology can be developed in this area in the near future.

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