Gastroenterology. 1998 Jul;115(1):139-46.

Three-dimensional structure of the major autoantigen in primary biliary cirrhosis.

Howard MJ, Fuller C, Broadhurst RW, Perham RN, Tang JG, Quinn J, Diamond AG, Yeaman SJ.

Source

Department of Biochemistry, Cambridge Centre for Molecular Recognition, University of Cambridge, England.

Abstract

BACKGROUND & AIMS:

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.

PMID:: 9649469; [PubMed - indexed for MEDLINE]

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Research Support, Non-U.S. Gov't

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Wellcome Trust/United Kingdom

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Related citations in PubMed

Structural requirement for autoreactivity on human pyruvate dehydrogenase-E2, the major autoantigen of primary biliary cirrhosis. Implication for a conformational autoepitope. [J Immunol. 1990]
Structural requirement for autoreactivity on human pyruvate dehydrogenase-E2, the major autoantigen of primary biliary cirrhosis. Implication for a conformational autoepitope.
Surh CD, Coppel R, Gershwin ME. J Immunol. 1990 May 1; 144(9):3367-74.
Reactivity of primary biliary cirrhosis sera with Escherichia coli dihydrolipoamide acetyltransferase (E2p): characterization of the main immunogenic region. [Proc Natl Acad Sci U S A. 1990]
Reactivity of primary biliary cirrhosis sera with Escherichia coli dihydrolipoamide acetyltransferase (E2p): characterization of the main immunogenic region.
Fussey SP, Ali ST, Guest JR, James OF, Bassendine MF, Yeaman SJ. Proc Natl Acad Sci U S A. 1990 May; 87(10):3987-91.
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Lipoylated and unlipoylated domains of human PDC-E2 as autoantigens in primary biliary cirrhosis: significance of lipoate attachment.
Quinn J, Diamond AG, Palmer JM, Bassendine MF, James OF, Yeaman SJ. Hepatology. 1993 Dec; 18(6):1384-91.
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Review [The association between autoantibodies to enzyme and diseases--with special reference to antibodies to pyruvate dehydrogenase complex (PDH)]. [Rinsho Byori. 1998]
Review [The association between autoantibodies to enzyme and diseases--with special reference to antibodies to pyruvate dehydrogenase complex (PDH)].
Moteki S, Amaki S, Nakano E. Rinsho Byori. 1998 Apr; 46(4):317-23.

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Cited by 10 PubMed Central articles

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Selmi C, Mackay IR, Gershwin ME. Immunol Cell Biol. 2011 Jan; 89(1):70-80. Epub 2010 Oct 26.
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Solution structure and characterisation of the human pyruvate dehydrogenase complex core assembly.
Vijayakrishnan S, Kelly SM, Gilbert RJ, Callow P, Bhella D, Forsyth T, Lindsay JG, Byron O. J Mol Biol. 2010 May 28; 399(1):71-93. Epub 2010 Mar 31.
Subunit and catalytic component stoichiometries of an in vitro reconstituted human pyruvate dehydrogenase complex. [J Biol Chem. 2009]
Subunit and catalytic component stoichiometries of an in vitro reconstituted human pyruvate dehydrogenase complex.
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Structures reported by this article

Inner Lipoyl Domain From Human Pyruvate Dehydrogenase (Pdh) Complex, Nmr, 1 Structure

PDB: 1FYC

Source: Homo sapiens

Method: Solution Nmr

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