Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling
Copyright policy )Modulation of the functional binding sites for TGF-β on the type II receptor leads to suppression of TGF-β signaling
Transforming growth factor-beta (TGF-beta) binds to two different types of serine/threonine kinase receptors termed type II (TbetaR-II) and type I (TbetaR-I). TGF-beta is unable to bind to TbetaR-I in the absence of TbetaR-II, and initiates receptor assembly by binding with high affinity to TbetaR-II. Previous structural analysis of the TGF-beta3-TbetaR-II complex has suggested that two charged amino acid residues, D55 and E142 of TbetaR-II, are binding sites of TGF-beta. In the present study, we have shown that mutations of the amino-acid residues, D55 and E142 of TbetaR-II, resulted in loss of TGF-beta binding and downstream signaling activity. Moreover, we found that 3,5,7,2',4'-pentahydroxyflavone (Morin) inhibits TGF-beta binding to TbetaR-II, and suppresses phosphorylation of Smad2 and expression of a TGF-beta target gene Smad7 induced by TGF-beta. Our findings may thus provide useful information for designing therapeutic agents for various diseases induced by TGF-beta, including advanced cancers.
Models, Molecular, Aspartic Acid, Binding Sites, Molecular Sequence Data, Glutamic Acid, Ligands, Cell Line, Protein Structure, Tertiary, Transforming Growth Factor beta, Chlorocebus aethiops, Mutation, Animals, Humans, Amino Acid Sequence, Protein Structure, Quaternary, Receptors, Transforming Growth Factor beta, Sequence Alignment, Conserved Sequence, Cell Proliferation, Signal Transduction
Models, Molecular, Aspartic Acid, Binding Sites, Molecular Sequence Data, Glutamic Acid, Ligands, Cell Line, Protein Structure, Tertiary, Transforming Growth Factor beta, Chlorocebus aethiops, Mutation, Animals, Humans, Amino Acid Sequence, Protein Structure, Quaternary, Receptors, Transforming Growth Factor beta, Sequence Alignment, Conserved Sequence, Cell Proliferation, Signal Transduction
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