Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.
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.
Groppe
Jay
J
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA. jgroppe@bcd.tamhsc.edu
Hinck
Cynthia S
CS
Samavarchi-Tehrani
Payman
P
Zubieta
Chloe
C
Schuermann
Jonathan P
JP
Taylor
Alexander B
AB
Schwarz
Patricia M
PM
Wrana
Jeffrey L
JL
Hinck
Andrew P
AP
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
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