The structural and functional determinants of the Axin and Dishevelled DIX domains.
BACKGROUND
The dishevelled and axin genes encode multi-domain proteins that play key roles in WNT signalling. Dishevelled prevents beta-catenin degradation by interfering with the interaction of beta-catenin with the degradation-mediating Axin-APC-GSK3beta complex. This interference leads to an accumulation of cytoplasmic beta-catenin, which enters the nucleus and interacts with transcription factors that induce expression of Wnt-target genes. Axin, as a component of the degradation-mediating complex, is a potent negative regulator of Wnt signalling, whereas Dishevelled is a potent activator. Both Dishevelled and Axin possess a DIX (Dishevelled/Axin) domain, which mediates protein-protein interactions, specifically homodimerization.


RESULTS
An evolutionary trace analysis of DIX domains identified conserved residues which, when mapped onto the crystal structure of the Axin DIX domain and a comparative model of the Dishevelled DIX domain, allow their categorization as residues of either structural or functional importance. We identify residues that are structural and functional determinants of the DIX domain fold, as well as those that are specific to homodimerization of Axin and Dishevelled.


CONCLUSIONS
This report provides the first explanation of the mutant phenotypes caused by non-synonymous substitutions in the Dishevelled and Axin DIX domain by correlating their presumed functional significance with molecular structure.
Ehebauer
Matthias T
MT
European Molecular Biology Laboratory, Notkestrasse 85, 22603 Hamburg, Germany. ehebauer@embl-hamburg.de
Arias
Alfonso Martinez
AM
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D019281:Dimerization; D000072261:Dishevelled Proteins; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry*; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry*; D016415:Sequence Alignment
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins