Solution structure of mouse Cripto CFC domain and its inactive variant Trp107Ala.
Luisa Calvanese1, Angela Saporito, Daniela Marasco
1Dipartimento di Chimica, Università Federico II, Complesso Universitario MSA, via Cintia 45, 80126 Napoli, Italy.
Journal of Medicinal Chemistry
|November 28, 2006
Summary
We determined the solution structures of the mouse Cripto CFC domain, revealing flexible, extended conformations. Key residues His104 and Trp107 are exposed, crucial for Alk4 receptor binding.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Cripto is a key developmental protein involved in cell signaling.
- The Cripto-Cryptic domain (CFC) mediates interactions with receptors like Alk4.
- Understanding CFC structure is vital for deciphering Cripto's biological roles.
Purpose of the Study:
- To elucidate the solution structures of the mouse Cripto CFC domain at different pH values.
- To investigate the structural impact of the W107A mutation on CFC's receptor binding capability.
- To identify structural features involved in Cripto-Alk4 receptor interaction.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy was employed to determine the 3D structures.
- Solution-state NMR data were collected at pH 3 and pH 6.
- Site-directed mutagenesis was used to create the W107A variant.
Main Results:
- The CFC domain exhibits a flexible and extended structure with three antiparallel strands and a conserved disulfide bond pattern (C1-C4, C2-C6, C3-C5).
- Histidine 104 and Tryptophan 107 side chains are solvent-exposed, supporting their role in Alk4 receptor binding.
- A hydrophobic patch on one side and a hydrophilic patch (in wild-type) on the other suggest roles in membrane interaction and receptor recognition, respectively.
Conclusions:
- The study provides the first solution structures of the mouse Cripto CFC domain, detailing its conformational flexibility.
- The W107A mutation's structural effects and the roles of specific residues in receptor binding and potential membrane interactions were elucidated.
- These findings offer insights into the molecular mechanisms of Cripto signaling and Alk4 receptor recognition.
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