title: Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.
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.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA. jgroppe@bcd.tamhsc.edu
authors.forename: Jay
authors.initials: J
authors.lastname: Groppe
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Hinck
authors.forename: Payman
authors.initials: P
authors.lastname: Samavarchi-Tehrani
authors.forename: Chloe
authors.initials: C
authors.lastname: Zubieta
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Schuermann
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Taylor
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Schwarz
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hinck
mesh_terms: D052004:Bone Morphogenetic Protein Receptors / Q000737:chemistry / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D053782:Transforming Growth Factor beta3 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D046912:Multiprotein Complexes; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053782:Transforming Growth Factor beta3; D052004:Bone Morphogenetic Protein Receptors