Abstract
Wnts have a structure resembling a hand with "thumb" and "index" fingers that grasp the cysteine rich domains of Frizzled receptors at two distinct binding sites. In the present work we show that the WIF domain of Wnt Inhibitory Factor 1 is also bound by Wnts at two sites. Using C-terminal domains of Wnt5a and Wnt7a and arginine-scanning mutagenesis of the WIF domain we demonstrate that, whereas the N-terminal, lipid-modified "thumb" of Wnts interacts with the alkyl-binding site of the WIF domain, the C-terminal domain of Wnts (Wnt-CTD) binds to a surface on the opposite side of the WIF domain.
Keywords:
Arginine-scanning mutagenesis; Cancer therapy; Homology modeling; Protein–protein interaction; Ryk receptor tyrosine kinase; WIF domain; Wnt; Wnt Inhibitory Factor 1.
Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence
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Arginine / chemistry
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Arginine / genetics
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Arginine / metabolism
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Binding Sites / genetics
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Humans
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Kinetics
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Protein Binding
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Protein Structure, Tertiary*
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Repressor Proteins / chemistry*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Wnt Proteins / chemistry*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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Wnt-5a Protein
Substances
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Adaptor Proteins, Signal Transducing
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Proto-Oncogene Proteins
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Recombinant Proteins
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Repressor Proteins
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WIF1 protein, human
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WNT5A protein, human
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WNT7A protein, human
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Wnt Proteins
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Wnt-5a Protein
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Arginine