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Science 287 (5450): 92-97

Copyright © 2000 by the American Association for the Advancement of Science

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

Geng Wu, 1* Ye-Guang Chen, 2* Barish Ozdamar, 3 Cassie A. Gyuricza, 1 P. Andrew Chong, 3 Jeffrey L. Wrana, 3 Joan Massagué, 2 Yigong Shi 1dagger

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.

1 Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, NJ 08544, USA.
2 Cell Biology Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
3 Program in Molecular Biology and Cancer, Department of Medical Genetics and Microbiology, University of Toronto, Room 1075, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada M5G 1X5.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: yshi{at}molbio.princeton.edu


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