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Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily
1Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Abstract:
The transforming growth factors-beta (TGF-beta 1 through -beta 5) are a family of homodimeric cytokines that regulate proliferation and function in many cell types. Family members have 66 to 80% sequence identity and nine strictly conserved cysteines. A crystal structure of a member of this family, TGF-beta 2, has been determined at 2.1 angstrom (A) resolution and refined to an R factor of 0.172. The monomer lacks a well-defined hydrophobic core and displays an unusual elongated nonglobular fold with dimensions of approximately 60 A by 20 A by 15 A. Eight cysteines form four intrachain disulfide bonds, which are clustered in a core region forming a network complementary to the network of hydrogen bonds. The dimer is stabilized by the ninth cysteine, which forms an interchain disulfide bond, and by two identical hydrophobic interfaces. Sequence profile analysis of other members of the TGF-beta superfamily, including the activins, inhibins, and several developmental factors, imply that they also adopt the TGF-beta fold.
Insights
The crystal structure of transforming growth factor-beta 2 (TGF-beta 2) reveals an elongated fold stabilized by disulfide bonds and hydrophobic interactions. This structure suggests other TGF-beta superfamily members share a similar fold, crucial for cell regulation.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Transforming growth factors-beta (TGF-beta) are critical cytokines regulating cell proliferation and function.
- Members of the TGF-beta family exhibit high sequence identity and conserved cysteines, suggesting conserved structural features.
Purpose of the Study:
- To determine the three-dimensional crystal structure of TGF-beta 2.
- To elucidate the structural basis for TGF-beta 2 dimerization and stability.
- To infer the conserved structural fold within the TGF-beta superfamily.
Main Methods:
- X-ray crystallography at 2.1 angstrom resolution.
- Refinement of the crystal structure.
- Sequence profile analysis of TGF-beta superfamily members.
Main Results:
- The TGF-beta 2 monomer exhibits an elongated, nonglobular fold (approx. 60x20x15 A) lacking a defined hydrophobic core.
- Eight cysteines form four intrachain disulfide bonds clustered in a core region.
- The dimer is stabilized by a ninth interchain disulfide bond and two hydrophobic interfaces.
Conclusions:
- The determined TGF-beta 2 structure provides insights into the molecular mechanisms of cytokine regulation.
- The unusual fold and stabilization by disulfide bonds are key features of TGF-beta 2.
- Sequence analysis implies that other TGF-beta superfamily members likely adopt a similar conserved fold.
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