Journal: J Biol Chem / Year: 2015 Title: Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease. Authors: Xi Chen / Kathrin Hnida / Melissa Ann Graewert / Jan Terje Andersen / Rasmus Iversen / Anne Tuukkanen / Dmitri Svergun / Ludvig M Sollid / Abstract: Antibodies to the autoantigen transglutaminase 2 (TG2) are a hallmark of celiac disease. We have studied the interaction between TG2 and an anti-TG2 antibody (679-14-E06) derived from a single gut ...Antibodies to the autoantigen transglutaminase 2 (TG2) are a hallmark of celiac disease. We have studied the interaction between TG2 and an anti-TG2 antibody (679-14-E06) derived from a single gut IgA plasma cell of a celiac disease patient. The antibody recognizes one of four identified epitopes targeted by antibodies of plasma cells of the disease lesion. The binding interface was identified by small angle x-ray scattering, ab initio and rigid body modeling using the known crystal structure of TG2 and the crystal structure of the antibody Fab fragment, which was solved at 2.4 Å resolution. The result was confirmed by testing binding of the antibody to TG2 mutants by ELISA and surface plasmon resonance. TG2 residues Arg-116 and His-134 were identified to be critical for binding of 679-14-E06 as well as other epitope 1 antibodies. In contrast, antibodies directed toward the two other main epitopes (epitopes 2 and 3) were not affected by these mutations. Molecular dynamics simulations suggest interactions of 679-14-E06 with the N-terminal domain of TG2 via the CDR2 and CDR3 loops of the heavy chain and the CDR2 loop of the light chain. In addition there were contacts of the framework 3 region of the heavy chain with the catalytic domain of TG2. The results provide an explanation for the biased usage of certain heavy and light chain gene segments by epitope 1-specific antibodies in celiac disease.
Instrument name: PETRA III P12 / City: Hamburg / 国: Germany / Type of source: X-ray synchrotron / Wavelength: 0.12 Å / Dist. spec. to detc.: 3.1 mm
Detector
Name: Pilatus 2M
Scan
Title: transglutaminase 2 (TG2 mixture) / Measurement date: Jan 17, 2015 / Storage temperature: 10 °C / Cell temperature: 10 °C / Exposure time: 0.05 sec. / Number of frames: 20 / Unit: 1/nm /
Min
Max
Q
0.0199
4.5094
Distance distribution function P(R)
Sofotware P(R): GNOM 5.0 / Number of points: 1096 /
Min
Max
Q
0.127957
3.0129
P(R) point
1
1096
R
0
12
Result
Type of curve: single_conc Comments: Structural basis for antigen recognition by transglutaminase 2-specific autoantibodies in celiac disease --- this is the scattering profile of TG2 by itself that is comprised primarilly of ...Comments: Structural basis for antigen recognition by transglutaminase 2-specific autoantibodies in celiac disease --- this is the scattering profile of TG2 by itself that is comprised primarilly of monomers and higher oligomeric species (monomer 92%; dimer 8% volume fraction.)
Experimental
Standard
Porod
MW
77 kDa
77 kDa
73 kDa
Volume
-
-
117 nm3
P(R)
P(R) error
Guinier
Guinier error
Forward scattering, I0
1913
15.3
1922
8
Radius of gyration, Rg
3.43 nm
0.02
3.38 nm
0.02
Min
Max
Error
D
-
12
0.5
Guinier point
32
139
-
+
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