Fc receptors, which are expressed on the majority of hematopoietic cells, play important roles in antibody-mediated immune responses. [3][4][5]. In addition to variations in affinity, each receptor displays distinct IgG subtype specificities. Unlike the high affinity receptors that can bind monomeric antibodies, the low affinity receptors preferentially bind to and are activated by immune complexes.Human Fc␥RIII exists as two isoforms, Fc␥RIIIA and Fc␥RIIIB, that share 96% sequence identity in their extracellular immunoglobulin-binding regions. Fc␥RIIIA is expressed on macrophages, mast cells, and natural killer cells as a transmembrane receptor. In contrast, Fc␥RIIIB, present exclusively on neutrophils, is anchored by a glycosyl-phosphatidylinositol linker to the plasma membrane. Although Fc␥RIIIA associates with the immunoreceptor tyrosine-based activation motif containing Fc⑀RI ␥-chain or the T cell receptor -chain for its signaling, Fc␥RIIIB lacks a signaling component. Nevertheless, it plays an active role in triggering Ca 2ϩ mobilization and in neutrophil degranulation (6, 7). In addition, Fc␥RIIIB, in conjunction with Fc␥RIIA, activates phagocytosis, degranulation, and the oxidative burst that leads to the clearance of opsonized pathogens by neutrophils. A soluble form of Fc␥RIIIB was reported to activate the CR3 complement receptordependent inflammatory process (8).The Fc binding region on Fc␥RII and Fc␥RIII has been identified through the work of chimeric receptors with Fc⑀RI as primarily the membrane proximal domain, including both the BC and FG loops. Further site-directed mutations have revealed several residues of the receptor critical to Fc binding (9 -11). Similar regions on the ␣-chain of Fc⑀RI were also identified to be critical for IgE binding affinity (12). The receptor binding site on Fc has been located through the construction of chimeric IgG molecules and mutational analysis at the lower hinge region, residues located in the hinge region between the C H 1 and C H 2 domains and immediately adjacent to the N terminus of the C H 2 domain of IgG (13-15). In particular, residues 234 -238 (Leu-Leu-Gly-Gly-Pro) of the lower hinge of IgG1 have been implicated in the receptor binding. The corresponding region of IgE has also been implicated in the Fc⑀RI binding (16). Apart from the lower hinge region, a few residues on the C H 2 domain of an IgG2b were also suggested to interact * This work was supported by the intramural research funding of NIAID, National Institutes of Health and by INSERM, Institut Curie, France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The recent crystal structures of Fc⑀RI␣, Fc␥RIIA, and Fc␥RIIB have each revealed a conserved Ig-like structure, with particularly the small hinge angle between the two Ig-like domains, which is unique to the Fc receptors (19 -21). We report here the crystal stru...

Transforming growth factor (TGF)-␤1, -␤2, and -␤3 are 25-kDa homodimeric polypeptides that play crucial nonoverlapping roles in embryogenesis, tissue development, carcinogenesis, and immune regulation. Here we report the 3.0-Å resolution crystal structure of the ternary complex between human TGF-␤1 and the extracellular domains of its type I and type II receptors, T␤RI and T␤RII. The TGF-␤1 ternary complex structure is similar to previously reported TGF-␤3 complex except with a 10°rotation in T␤RI docking orientation. Quantitative binding studies showed distinct kinetics between the receptors and the isoforms of TGF-␤. T␤RI showed significant binding to TGF-␤2 and TGF-␤3 but not TGF-␤1, and the binding to all three isoforms of TGF-␤ was enhanced considerably in the presence of T␤RII. The preference of TGF-␤2 to T␤RI suggests a variation in its receptor recruitment in vivo. Although TGF-␤1 and TGF-␤3 bind and assemble their ternary complexes in a similar manner, their structural differences together with differences in the affinities and kinetics of their receptor binding may underlie their unique biological activities. Structural comparisons revealed that the receptor-ligand pairing in the TGF-␤ superfamily is dictated by unique insertions, deletions, and disulfide bonds rather than amino acid conservation at the interface. The binding mode of T␤RII on TGF-␤ is unique to TGF-␤s, whereas that of type II receptor for bone morphogenetic protein on bone morphogenetic protein appears common to all other cytokines in the superfamily. Further, extensive hydrogen bonds and salt bridges are present at the high affinity cytokine-receptor interfaces, whereas hydrophobic interactions dominate the low affinity receptor-ligand interfaces.Transforming growth factor (TGF)-␤ 2 isoforms regulate the growth and differentiation of many cell types involved in normal development, immune function, and carcinogenesis (1-3). TGF-␤s are the founding members of a highly diversified family of signaling ligands and receptors, known as the TGF-␤ superfamily. To date the superfamily consists of more than 30 growth factors and cytokines, including TGF-␤s, bone morphogenetic proteins (BMPs), activins, inhibins, nodal, Müllerian inhibiting substance, growth differentiation factors, and others (4). TGF-␤s and related factors signal through two single-pass transmembrane receptors, known as the type I and type II receptors. These two receptor types have the same overall domain structure, including an extracellular ligand-binding domain displaying a three-finger toxin fold, a single transmembrane helix, and a cytosolic serine-threonine kinase domain. Signaling is initiated by the ligand, which binds the receptor extracellular domains, bringing them together and triggering a phosphorylation cascade, whereby the type II phosphorylates the type I, and the type I phosphorylates Smads, the cytoplasmic effectors of the pathway (3).Specificities have been determined based on cell-based affinity labeling studies with radiolabeled ligands and have enabled th...

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