Abstract
The Smad proteins mediate transforming growth factor-beta (TGFbeta) signaling from the transmembrane serine-threonine receptor kinases to the nucleus. The Smad anchor for receptor activation (SARA) recruits Smad2 to the TGFbeta receptors for phosphorylation. The crystal structure of a Smad2 MH2 domain in complex with the Smad-binding domain (SBD) of SARA has been determined at 2.2 angstrom resolution. SARA SBD, in an extended conformation comprising a rigid coil, an alpha helix, and a beta strand, interacts with the beta sheet and the three-helix bundle of Smad2. Recognition between the SARA rigid coil and the Smad2 beta sheet is essential for specificity, whereas interactions between the SARA beta strand and the Smad2 three-helix bundle contribute significantly to binding affinity. Comparison of the structures between Smad2 and a comediator Smad suggests a model for how receptor-regulated Smads are recognized by the type I receptors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activin Receptors, Type I*
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Amino Acid Sequence
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Binding Sites
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Carrier Proteins / chemistry*
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Carrier Proteins / metabolism*
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Crystallography, X-Ray
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Hydrogen Bonding
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Phosphorylation
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Point Mutation
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Protein Conformation
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / chemistry
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Smad2 Protein
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Trans-Activators / chemistry*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Zinc Fingers
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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Smad2 Protein
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Trans-Activators
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I