Title

Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

8-3-2002

Document Type

Article

Subjects

Allosteric Regulation; Amino Acid Sequence; Binding Sites; Carrier Proteins; Crystallography, X-Ray; DNA-Binding Proteins; Dimerization; Enzyme Activation; Humans; Hydrophobicity; *Intracellular Signaling Peptides and Proteins; Macromolecular Substances; Models, Molecular; Molecular Sequence Data; Phosphorylation; Protein Conformation; Protein Interaction Mapping; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins; Receptors, Transforming Growth Factor beta; *Serine Endopeptidases; Smad3 Protein; Trans-Activators; Transcription, Genetic

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Smad3 transduces the signals of TGF-betas, coupling transmembrane receptor kinase activation to transcriptional control. The membrane-associated molecule SARA (Smad Anchor for Receptor Activation) recruits Smad3 for phosphorylation by the receptor kinase. Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski. Here, we show that SARA and Ski recognize specifically the monomeric and trimeric forms of Smad3, respectively. Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-beta signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski. Structural models of the Smad3/SARA/receptor kinase complex and Smad3/Ski complex provide insights into the molecular basis of regulation.

Rights and Permissions

Citation: Genes Dev. 2002 Aug 1;16(15):1950-63. Link to article on publisher's site

DOI of Published Version

10.1101/gad.1002002

Related Resources

Link to Article in PubMed

Journal Title

Genes and development

PubMed ID

12154125