Cooperative Assembly of TGF-β Superfamily Signaling Complexes Is Mediated by Two Disparate Mechanisms and Distinct Modes of Receptor Binding

Jay Groppe, Cynthia S. Hinck, Payman Samavarchi-Tehrani, Chloe Zubieta, Jonathan P. Schuermann, Alexander B. Taylor, Patricia M. Schwarz, Jeffrey L. Wrana, Andrew P. Hinck

Research output: Contribution to journalArticle

171 Scopus citations

Abstract

Dimeric ligands of the transforming growth factor-β (TGF-β) superfamily signal across cell membranes in a distinctive manner by assembling heterotetrameric complexes of structurally related serine/threonine-kinase receptor pairs. Unlike complexes of the bone morphogenetic protein (BMP) branch that apparently form due to avidity from membrane localization, TGF-β complexes assemble cooperatively through recruitment of the low-affinity (type I) receptor by the ligand-bound high-affinity (type II) pair. Here we report the crystal structure of TGF-β3 in complex with the extracellular domains of both pairs of receptors, revealing that the type I docks and becomes tethered via unique extensions at a composite ligand-type II interface. Disrupting the receptor-receptor interactions conferred by these extensions abolishes assembly of the signaling complex and signal transduction (Smad activation). Although structurally similar, BMP and TGF-β receptors bind in dramatically different modes, mediating graded and switch-like assembly mechanisms that may have coevolved with branch-specific groups of cytoplasmic effectors.

Original languageEnglish (US)
Pages (from-to)157-168
Number of pages12
JournalMolecular Cell
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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