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Trends Biochem Sci. 2015 Jun;40(6):296-308. doi: 10.1016/j.tibs.2015.03.012. Epub 2015 Apr 29.

Structural determinants of Smad function in TGF-β signaling.

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Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain. Electronic address:
Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:


Smad transcription factors are central to the signal transduction pathway that mediates the numerous effects of the transforming growth factor β (TGF-β) superfamily of cytokines in metazoan embryo development as well as in adult tissue regeneration and homeostasis. Although Smad proteins are conserved, recent genome-sequencing projects have revealed their sequence variation in metazoan evolution, human polymorphisms, and cancer. Structural studies of Smads bound to partner proteins and target DNA provide a framework for understanding the significance of these evolutionary and pathologic sequence variations. We synthesize the extant mutational and structural data to suggest how genetic variation in Smads may affect the structure, regulation, and function of these proteins. We also present a web application that compares Smad sequences and displays Smad protein structures and their disease-associated variants.


Smad DNA binding; Smad conservation/variation; Smad proteins; Smad structure; Smad-binding proteins; TGF-β signaling; cancer mutations

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