13 Structural Basis for TGF-β Family Receptor Assembly and Signaling Specificity

Abstract

The transforming growth factor-β (TGF-β) family ligands initiate signaling by binding to, and forming a complex with, two types of transmembrane serine-threonine kinase receptors. Although some bone morphogenetic protein (BMP) ligands show a higher affinity for the type I receptors than for the type II receptors, many ligands, most notably TGF-βs and activins, exhibit a higher affinity for the type II receptors than for the type I receptors (Miyazono et al. 2001). Ligand binding to a receptor type then facilitates and stabilizes the interaction with the complementary receptor, thus forming the ternary ligand-receptor complex, in which the constitutively active type II receptor kinases phosphorylate and thereby activate the type I receptor kinases (see Chapter 6). The activated type I receptor kinases directly phosphorylate their downstream signal mediators, the receptor-activated Smads (R-Smads), which upon phosphorylation form heteromeric complexes with Smad4 (Lagna et al. 1996; Zhang et al. 1996). These translocate into the nucleus, where they bind to target promoters and cooperate with other transcription factors and coactivators and/or corepressors to regulate gene expression (Roberts 1999; Attisano and Wrana 2000; Massagué and Wotton 2000). The structural elucidation of the receptor-ligand assembly complex and the intermediates along this Smad-mediated pathway has provided a snapshot of the signaling engine at the atomic level (Shi and Massagué 2003) and provides insight into how signaling specificity is conveyed in the system.

EXTRACELLULAR LIGAND-RECEPTOR INTERACTIONS
Structural Features of the Ligands
The overall conformations for most of the TGF-β family of ligands, determined in their unbound state, are...