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. 2002 Mar 5;99(5):2743-7.
doi: 10.1073/pnas.042454899. Epub 2002 Feb 26.

Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity

Shenping Liu  1 , Richard A Cerione, Jon Clardy
Affiliations

Structural basis for the guanine nucleotide-binding activity of tissue transglutaminase and its regulation of transamidation activity

Shenping Liu et al. Proc Natl Acad Sci U S A. .

Abstract

Tissue transglutaminase (TG) is a Ca2+-dependent acyltransferase with roles in cellular differentiation, apoptosis, and other biological functions. In addition to being a transamidase, TG undergoes a GTP-binding/GTPase cycle even though it lacks any obvious sequence similarity with canonical GTP-binding (G) proteins. Guanine nucleotide binding and Ca2+ concentration reciprocally regulate TG's transamidation activity, with nucleotide binding being the negative regulator. Here we report the x-ray structure determined to 2.8-A resolution of human TG complexed with GDP. Although the transamidation active site is similar to those of other known transglutaminases, the guanine nucleotide-binding site of TG differs markedly from other G proteins. The structure suggests a structural basis for the negative regulation of transamidation activity by bound nucleotide, and the positive regulation of transamidation by Ca2+.

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Figures

Scheme 1
Scheme 1
Figure 1
Figure 1
Overall structure of a human tissue transglutaminase (TG) dimer with bound GDP. TG is shown in ribbon drawing with the β-sandwich domain, the catalytic core domain, and the first and second β-barrel domain shown in green, red, cyan, and yellow, respectively. The loops connecting the first β-barrel domain to the catalytic core and the second β-barrel are shown in purple. GDP is shown as a ball-and-stick model between the catalytic core and the first β-barrel. The picture was prepared with MOLSCRIPT (44) and RASTER3D (45).
Figure 2
Figure 2
Stereoview of an electron density map (2Fo − Fc, 1.2σ, GDP omitted, 2.8-Å resolution) of the GDP-binding pocket. An atomic model of the final structure is embedded in the electron density. Drawing prepared from MOLSCRIPT (44) and RASTER3D (45).
Figure 3
Figure 3
Comparisons between the atomic interactions of GDP with TG (Left) and Ras (Right). Hydrogen bonds and ion pair interactions are shown in dashed lines. The GDP molecule is shown in ball-and-stick. TG and Ras residues are shown in thin sticks. Drawing prepared with MOLSCRIPT (44) and RASTER3D (45).
Figure 4
Figure 4
Sequence alignment of different members of the human transglutaminase family with TG numbering on the bottom. F13A represents factor XIIIa and B4.2 represents the erythrocyte band 4.2 protein. Conserved residues are in pink; TG catalytic triad residues (Cys-277, His-335, Asp-358) and Tyr-516 are indicated with triangles; residues that interact with bound GDP are indicated with circles. Figure prepared with alscript (46).
Figure 5
Figure 5
Transamidation active site of TG. A close-up view of the juxtaposition of the catalytic triad consisting of Cys-277–His-335–Asp-358 and Tyr-516 relative to the guanine nucleotide-binding site. Cys-277, His-335, Asp-358, Tyr-516, and GDP are shown in ball-and-stick. Tyr-516 points toward Cys-277, the catalytic nucleophile, in the active site. The drawing was prepared by using MOLSCRIPT (44) and RASTER3D (45).
Figure 6
Figure 6
Comparison of the calcium-binding sites of TG (green) and factor XIIIa (red). In factor XIIIa, the loop involved in calcium binding is oriented toward the Ca2+-binding site, whereas in TG-GDP, the same loop is oriented toward GDP. Figure prepared with MOLSCRIPT (44) and RASTER3D (45).
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