Structural Basis of Smad2 Recognition by the Smad Anchor for Receptor Activation

• Published in: Science (American Association for the Advancement of Science) 2000-01, Vol.287 (5450), p.92-97
• Main Authors: Wu, Geng, Chen, Ye-Guang, Ozdamar, Barish, Gyuricza, Cassie A., Chong, P. Andrew, Wrana, Jeffrey L., Massagué, Joan, Shi, Yigong
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I; Amides; Amino Acid Sequence; Atoms; Binding Sites; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cell physiology; Crystal structure; Crystallography, X-Ray; Crystals; Datasets; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Hydrogen Bonding; Individualized Instruction; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Mutation; Phosphorylation; Point Mutation; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Receptor, Transforming Growth Factor-beta Type I; Receptors; Receptors, Transforming Growth Factor beta - chemistry; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Responses to growth factors, tumor promotors, other factors; SARA protein; Scientific Concepts; Signal Transduction; Smad proteins; Smad2 Protein; Solitons; Structural Elements (Construction); Surface areas; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; transforming growth factor-^b; Zinc Fingers
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.287.5450.92

The Smad proteins mediate transforming growth factor-β (TGFβ) signaling from the transmembrane serine-threonine receptor kinases to the nucleus. The Smad anchor for receptor activation (SARA) recruits Smad2 to the TGFβ 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 α helix, and a β strand, interacts with the β sheet and the three-helix bundle of Smad2. Recognition between the SARA rigid coil and the Smad2 β sheet is essential for specificity, whereas interactions between the SARA β 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.