TY - JOUR
T1 - Crystal structure of the human TβR2 ectodomain-TGF-β3 complex
AU - Hart, P. John
AU - Deep, Shashank
AU - Taylor, Alexander B.
AU - Shu, Zhanyong
AU - Hinck, Cynthia S.
AU - Hinck, Andrew P.
PY - 2002
Y1 - 2002
N2 - Transforming growth factor-β (TGF-β) 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-β initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 Å crystal structure of the extracellular ligand-binding domain of the human TGF-β type II receptor (ecTβR2) in complex with human TGF-β3. ecTβR2 interacts with homodimeric TGF-β3 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, ecTβR2-bound TGF-β3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-β3 binding shown by ecTβR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-β binding to the type I receptor ectodomain (ecTβR1), suggests an assembly mechanism in which ecTβR1 and ecTβR2 bind at adjacent positions on the ligand surface and directly contact each other via proteinprotein interactions.
AB - Transforming growth factor-β (TGF-β) 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-β initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 Å crystal structure of the extracellular ligand-binding domain of the human TGF-β type II receptor (ecTβR2) in complex with human TGF-β3. ecTβR2 interacts with homodimeric TGF-β3 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, ecTβR2-bound TGF-β3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-β3 binding shown by ecTβR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-β binding to the type I receptor ectodomain (ecTβR1), suggests an assembly mechanism in which ecTβR1 and ecTβR2 bind at adjacent positions on the ligand surface and directly contact each other via proteinprotein interactions.
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U2 - 10.1038/nsb766
DO - 10.1038/nsb766
M3 - Article
C2 - 11850637
AN - SCOPUS:0036177334
SN - 1072-8368
VL - 9
SP - 203
EP - 208
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 3
ER -