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Characterization of the
structure and function of W --> F WW domain variants: identification
of a natively unfolded protein that folds upon ligand
binding.
Koepf EK, Petrassi HM, Ratnaswamy G, Huff
ME, Sudol M, Kelly JW.
Department of Chemistry, The Skaggs
Institute of Chemical Biology, The Scripps Research Institute, La Jolla,
California 92037, USA.
The WW domain adopts a compact,
three-stranded, antiparallel beta-sheet structure that mediates
protein-protein interactions by binding to xPPxY-based protein ligands,
such as the PY-ligand (EYPPYPPPPYPSG) derived from p53 binding
protein-2. The conserved Trp residues, after which this domain was
named, were replaced with Phe so their importance in structural
integrity and for ligand binding could be evaluated. A biophysical
approach was employed to compare the W17F, W39F, and W17F/W39F WW
domains to the wild-type protein. The data demonstrate that replacement
of Trp39 with Phe (W39F) does not disrupt the structure of the WW domain
variant, but does abolish ligand binding. In contrast, the W17F WW
domain variant is largely if not completely unfolded; however, this
variant undergoes a PY-ligand induced disorder to order (folding)
transition. The dissociation constant for the W17F WW domain-PY-ligand
interaction is 15.1 +/- 1.2 microM, only slightly higher than that
observed for the wild-type WW domain interaction (5.9 +/- 0.33 microM).
The W17F WW domain is a natively unfolded protein which adopts a native
conformation upon PY-ligand binding.
PMID: 10572009 [PubMed -
indexed for MEDLINE]
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