Crystal structure of the human TβR2 ectodomain–TGF-β3 complex

Hart, P. John; Deep, Shashank; Taylor, Alexander B.; Shu, Zhang; Hinck, Cynthia S.; Hinck, Andrew P.

doi:10.1038/nsb766

Cited by 148 publications

(274 citation statements)

References 40 publications

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“…This unresolved region is in close proximity to residues in the type II receptor that interact with TGF-␤3 (25), and could conceivably participate in altering ligand binding properties of the receptor. However, these prior studies were performed in COS cells, which express T␤RIII (11,12), and thus could not demonstrate the ability of T␤RII or T␤RII-B to bind TGF-␤2 in the absence of T␤RIII.…”

Section: Discussionmentioning

confidence: 99%

“…terminus of the type II-B receptor, and would be in the unresolved region of the crystal structure of the ECD of the type II receptor (25). This unresolved region is in close proximity to residues in the type II receptor that interact with TGF-␤3 (25), and could conceivably participate in altering ligand binding properties of the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…The high resolution crystal structures of TGF-␤2 (21,22), TGF-␤3 (23), and more recently, the soluble ECD of the type II receptor (24), and the complex of the ECD-T␤RII and TGF-␤3 (25) have been solved, in addition to those of the BMPR1A⅐BMP2 (26) and ActRII⅐BMP7 complexes (27). In aggregate, these studies suggest that TGF-␤ receptor and ligand interactions may involve a cooperative model of binding with direct protein-protein contact between the type II and type I receptors as part of the assembly process, whereas the BMP/ActRII and BMP ligands may utilize an allosteric model of binding in which the type II and type I receptors do not necessarily make contact with each other.…”

Section: Discussionmentioning

confidence: 99%

“…The crystal structures of TGF-␤2 (21,22), and TGF-␤3 (23) ligands have been solved. In addition, the extracellular domain of T␤RII alone (24), and in complex with TGF-␤3 (25), have also been crystallized. These structures yield qualitatively different information than the crystal structure of the BMP type IA receptor (BMPR1A)⅐ BMP-2 complex (26) and the activin type II receptor (ActRII)⅐ BMP-7 complex (27).…”

mentioning

confidence: 99%

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In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Babitt

Pirani

et al. 2004

Journal of Biological Chemistry

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Transforming growth factor ␤ (TGF-␤) ligands exert their biological effects through type II (T␤RII) and type I receptors (T␤RI). Unlike TGF-␤1 and -␤3, TGF-␤2 appears to require the co-receptor betaglycan (type III receptor, T␤RIII) for high affinity binding and signaling. Recently, the T␤RIII null mouse was generated and revealed significant non-overlapping phenotypes with the TGF-␤2 null mouse, implying the existence of T␤RIII independent mechanisms for TGF-␤2 signaling. Because a variant of the type II receptor, the type II-B receptor (T␤RII-B), has been suggested to mediate TGF-␤2 signaling in the absence of T␤RIII, we directly tested the ability of T␤RII-B to bind TGF-␤2. Here we show that the soluble extracellular domain of the type II-B receptor (sT␤RII-B.Fc) bound TGF-␤1 and TGF-␤3 with high affinity (K d values ‫؍‬ 31.7 ؎ 22.8 and 74.6 ؎ 15.8 pM, respectively), but TGF-␤2 binding was undetectable at corresponding doses. Similar results were obtained for the soluble type II receptor (sT␤RII.Fc). However, sT␤RII.Fc or sT␤RII-B.Fc in combination with soluble type I receptor (sT␤RI.Fc) formed a high affinity complex that bound TGF-␤2, and this complex inhibited TGF-␤2 in a biological inhibition assay. These results show that TGF-␤2 has the potential to signal in the absence of T␤RIII when sufficient TGF-␤2, T␤RI, and T␤RII or T␤RII-B are present. Our data also support a cooperative model for receptor-ligand interactions, as has been suggested by crystallization studies of TGF-␤ receptors and ligands. Our cell-free binding assay system will allow for testing of models of receptor-ligand complexes prior to actual solution of crystal structures.Transforming growth factor-␤ (TGF-␤) 1 represents a large superfamily of dimeric growth factors that include the TGF-␤s, inhibins, activins, Mullerian inhibiting substance, growth and differentiation factors, and bone morphogenetic proteins (BMPs) in mammals (1, 2). These cytokines play important roles in an array of processes such as growth, differentiation, and development (3). There are three TGF-␤ isoforms that share a high degree of homology and overlapping biological activities (4). However, distinct expression patterns and unique, isoform-specific phenotypes of the corresponding knockout mice demonstrate significant non-redundancy of TGF-␤ function (5-9).TGF-␤s exert their biological effects through three cell surface receptors designated as type I, II, and III (T␤RI, T␤RII, and T␤RIII) (2), all of which have been cloned (10 -13). In addition, the type II-B receptor (T␤RII-B), an alternatively spliced isoform of T␤RII containing an insert of 26 amino acids replacing Val 51 , has also been identified (14 -16). Type I and type II receptors have intracellular serine/threonine kinase domains, whereas the type III receptor has only a short intracellular domain. On binding of TGF-␤ ligands, constitutively active type II receptors recruit and phosphorylate type I receptors; the activated type I receptor kinase then interacts with and phosphorylates downstream signaling ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Babitt

Pirani

et al. 2004

Journal of Biological Chemistry

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“…27 Amino acids 92-98 regulate binding of TGF-β to the TGF-β type II receptor (TβRII), 28 with amino acid 94 directly binding TβRII. 29,30 …”

Section: Tgf-β Synthesismentioning

confidence: 99%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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Transforming growth factor-β (TGF-β) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-βs useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-β has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-β have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-β activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.

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Overview of Protein Structural and Functional Folds

2004

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This overview provides an illustrated, comprehensive survey of some commonly observed protein-fold families and structural motifs, chosen for their functional significance. It opens with descriptions and definitions of the various elements of protein structure and associated terminology. Following is an introduction into web-based structural bioinformatics that includes surveys of interactive web servers for protein fold or domain annotation, protein-structure databases, protein-structure-classification databases, structural alignments of proteins, and molecular graphics programs available for personal computers. The rest of the overview describes selected families of protein folds in terms of their secondary, tertiary, and quaternary structural arrangements, including ribbon-diagram examples, tables of representative structures with references, and brief explanations pointing out their respective biological and functional significance.

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Crystal structure of the human TβR2 ectodomain–TGF-β3 complex

Cited by 148 publications

References 40 publications

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Medical Applications of Transforming Growth Factor-

Overview of Protein Structural and Functional Folds

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