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WW domains mediate protein recognition, usually though binding to proline-rich sequences. In many proteins, WW domains occur in tandem arrays. Whether or how individual domains within such arrays cooperate to recognize biological partners is, as yet, poorly characterized. An important question is whether functional diversity of different WW domain proteins is reflected in the structural organization and ligand interaction mechanisms of their multiple domains. We have determined the solution structure and dynamics of a pair of WW domains (WW3-4) from a Drosophila Nedd4 family protein called Suppressor of deltex (Su(dx)), a regulator of Notch receptor signaling. We find that the binding of a type 1 PPPY ligand to WW3 stabilizes the structure with effects propagating to the WW4 domain, a domain that is not active for ligand binding. Both WW domains adopt the characteristic triple-stranded beta-sheet structure, and significantly, this is the first example of a WW domain structure to include a domain (WW4) lacking the second conserved Trp (replaced by Phe). The domains are connected by a flexible linker, which allows a hinge-like motion of domains that may be important for the recognition of functionally relevant targets. Our results contrast markedly with those of the only previously determined three-dimensional structure of tandem WW domains, that of the rigidly oriented WW domain pair from the RNA-splicing factor Prp40. Our data illustrate that arrays of WW domains can exhibit a variety of higher order structures and ligand interaction mechanisms.

Original publication




Journal article


J Biol Chem

Publication Date





34991 - 35000


Amino Acid Sequence, Animals, DNA, Complementary, Drosophila, Drosophila Proteins, Drosophila melanogaster, Ligands, Magnetic Resonance Spectroscopy, Membrane Proteins, Models, Molecular, Molecular Sequence Data, Peptides, Phenylalanine, Protein Binding, Protein Structure, Tertiary, Receptors, Notch, Sequence Homology, Amino Acid, Spectrometry, Fluorescence, Tryptophan, Ubiquitin-Protein Ligases