Crystal structure of the human TbetaR2 ectodomain--TGF-beta3 complex.
Transforming growth factor-beta (TGF-beta) is the prototype of a large family of structurally related cytokines that play key roles in maintaining cellular homeostasis by signaling through two classes of functionally distinct Ser/Thr kinase receptors, designated as type I and type II. TGF-beta initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 A crystal structure of the extracellular ligand-binding domain of the human TGF-beta type II receptor (ecTbetaR2) in complex with human TGF-beta3. ecTbetaR2 interacts with homodimeric TGF-beta3 by binding identical finger segments at opposite ends of the growth factor. Relative to the canonical 'closed' conformation previously observed in ligand structures across the superfamily, ecTbetaR2-bound TGF-beta3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-beta3 binding shown by ecTbetaR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-beta binding to the type I receptor ectodomain (ecTbetaR1), suggests an assembly mechanism in which ecTbetaR1 and ecTbetaR2 bind at adjacent positions on the ligand surface and directly contact each other via protein--protein interactions.
Hart
P John
PJ
Department of Biochemistry and Center for Biomolecular Structure Analysis, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
Deep
Shashank
S
Taylor
Alexander B
AB
Shu
Zhanyong
Z
Hinck
Cynthia S
CS
Hinck
Andrew P
AP
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism*; D053782:Transforming Growth Factor beta3
D008024:Ligands; D021122:Protein Subunits; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II