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

Kai Lin, Senyon Choe


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.

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

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