Three-dimensional structure of the major autoantigen in primary biliary cirrhosis.
OBJECTIVE
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. The major autoantigen, recognized by antibodies from > 95% of patients with PBC, has been identified as the E2 component (E2p) of the pyruvate dehydrogenase multienzyme complex. Immunodominant sites on E2p have been localized to the inner of the two lipoyl domains, where the essential cofactor lipoic acid is attached covalently. The aim of this study was to determine the three-dimensional structure of the inner lipoyl domain of human E2p.


METHODS
The domain was expressed in Escherichia coli; after purification, its structure was analyzed using nuclear magnetic resonance spectroscopy.


RESULTS
The structure of the lipoyl domain from human E2p was determined, and the implications of the structure for autoimmune recognition were assessed.


CONCLUSIONS
Knowledge of the structure further defines the major epitope and may help in the design of antigen-specific immunotherapy for treatment of PBC.
Howard
M J
MJ
Department of Biochemistry, Cambridge Centre for Molecular Recognition, University of Cambridge, England.
Fuller
C
C
Broadhurst
R W
RW
Perham
R N
RN
Tang
J G
JG
Quinn
J
J
Diamond
A G
AG
Yeaman
S J
SJ
D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry
D001324:Autoantigens; D011994:Recombinant Proteins