Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding

Mol Cell. 2008 Feb 1;29(2):157-68. doi: 10.1016/j.molcel.2007.11.039.

Abstract

Dimeric ligands of the transforming growth factor-beta (TGF-beta) 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-beta 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-beta3 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-beta receptors bind in dramatically different modes, mediating graded and switch-like assembly mechanisms that may have coevolved with branch-specific groups of cytoplasmic effectors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein Receptors / chemistry
  • Bone Morphogenetic Protein Receptors / metabolism
  • Bone Morphogenetic Proteins / chemistry
  • Bone Morphogenetic Proteins / metabolism
  • Cell Membrane / metabolism
  • Crystallography, X-Ray
  • Humans
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism
  • Protein Structure, Quaternary / physiology
  • Receptors, Transforming Growth Factor beta / chemistry*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / physiology
  • Smad Proteins / metabolism
  • Structure-Activity Relationship
  • Transforming Growth Factor beta3 / chemistry*
  • Transforming Growth Factor beta3 / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Multiprotein Complexes
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins
  • Transforming Growth Factor beta3
  • Bone Morphogenetic Protein Receptors

Associated data

  • PDB/2PJY