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

Howard, Mark J.; Fuller, Christopher; Broadhurst, R. William; Rn, Perham; Jg, Tang; Quinn, Janet; Diamond, AG; Yeaman, SJ

doi:10.1016/s0016-5085(98)70375-0

Cited by 76 publications

(72 citation statements)

References 32 publications

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“…Our interpretation of the epitope structure for anti-PDC-E2 has been facilitated by the derivation of an NMR structure for aa 131-233 of human PDC-E2 that encompasses the major immunodominant epitope(s) (22) (Fig. 2a).…”

Section: Discussionmentioning

confidence: 99%

Prediction of the Immunodominant Epitope of the Pyruvate Dehydrogenase Complex E2 in Primary Biliary Cirrhosis Using Phage Display

Rowley

Scealy

Whisstock

et al. 2000

The Journal of Immunology

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Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by autoantibodies reactive with the pyruvate dehydrogenase complex. A conformational epitope has been mapped to aa 91–227 within the inner lipoyl domain of the E2 subunit (pyruvate dehydrogenase complex E2 (PDC-E2)). We have used phage display to further localize this epitope. A random heptapeptide library was screened using IgG from two patients with PBC, with negative selection using pooled normal IgG. Phage that contained peptide inserts (phagotopes) selected using PBC sera differed from those selected using IgG from patients with RA or polychondritis. Two motifs occurred only among the PBC-selected phagotopes; these were MH (13 sequences, 16 phagotopes) and FV (FVEHTRW, FVEIYSP, FVLPWRI). The phagotopes selected were tested for reactivity with anti-PDC-E2 affinity purified from four patients with PBC. Phagotopes that contained 1 of 15 different peptide sequences were reactive with one or more of these four anti-PDC-E2 preparations, whereas phagotopes that contained 1of the remaining 28 sequences were negative. The peptides (FVLPWRI, MHLNTPP, MHLTQSP) encoded by three phagotopes that were strongly reactive with all four preparations of anti-PDC-E2 were synthesized. Each of the selected peptides, but not an irrelevant peptide, inhibited the reactivity by ELISA of PBC serum with recombinant PDC-E2 and reduced the inhibition of the enzyme activity of PDC by a PBC serum. The peptide sequences, along with the known NMR structure of the inner lipoyl domain of PDC-E2, allow the prediction of nonsequential residues 131HM132 and 178FEV180 that contribute to a conformational epitope.

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Section: Discussionmentioning

confidence: 99%

Prediction of the Immunodominant Epitope of the Pyruvate Dehydrogenase Complex E2 in Primary Biliary Cirrhosis Using Phage Display

Rowley

Scealy

Whisstock

et al. 2000

The Journal of Immunology

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“…The AMA antigens are different epitopes of the pyruvate dehydrogenase complex (PDC), especially the PDC-E2 [106,107] . Mitochondrial antigens are expressed in all nucleated cells, and AMAs are classically detected by IIF.…”

Section: Autoantibodies Specific To Liver Diseases Other Than Pscmentioning

confidence: 99%

Autoantibodies in primary sclerosing cholangitis

Hov¹,

Boberg²,

Karlsen³

2008

WJG

150

100

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The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients, but the specificity of these antibodies is generally low, and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecific dysregulation of the immune system, but the literature in PSC points to the possible presence of specific antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC, with a particular emphasis on the prevalence, clinical relevance and possible pathogenetic importance of each individual marker.

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“…The nuclear magnetic resonance (NMR) solution structures of the single E. coli E2o (Ricaud et al, 1996) and the innermost of the three E. coli E2p (Jones et al, 2000a) lipoyl domains have been solved, as have those of others from various other organisms (Dardel et al, 1993;Berg et al, 1996Berg et al, , 1997Howard et al, 1998). Their overall backbone structure is virtually identical, comprising a b-barrel formed from two four-stranded b-sheets.…”

Section: Introductionmentioning

confidence: 99%

Recognition of the lipoyl domain is the ultimate determinant of substrate channelling in the pyruvate dehydrogenase multienzyme complex

Jones

Stott

Reche

et al. 2001

Journal of Molecular Biology

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Reductive acetylation of the lipoyl domain (E2plip) of the dihydrolipoyl acetyltransferase component of the pyruvate dehydrogenase multienzyme complex of Escherichia coli is catalysed speci®cally by its partner pyruvate decarboxylase (E1p), and no productive interaction occurs with the analogous 2-oxoglutarate decarboxylase (E1o) of the 2-oxoglutarate dehydrogenase complex. Residues in the lipoyl-lysine b-turn region of the unlipoylated E2plip domain (E2plip apo ) undergo signi®cant changes in both chemical shift and transverse relaxation time (T 2 ) in the presence of E1p but not E1o. Residue Gly11, in a prominent surface loop between b-strands 1 and 2 in the E2plip domain, was also observed to undergo a signi®cant change in chemical shift. Addition of pyruvate to the mixture of E2plip apo and E1p caused larger changes in chemical shift and the appearance of multiple cross-peaks for certain residues, suggesting that the domain was experiencing more than one type of interaction. Residues in both b-strands 4 and 5, together with those in the prominent surface loop and the following b-strand 2, appeared to be interacting with E1p, as did a small patch of residues centred around Glu31. The values of T 2 across the polypeptide chain backbone were also lower than in the presence of E1p alone, suggesting that E2plip apo binds more tightly after the addition of pyruvate. The lipoylated domain (E2plip holo ) also exhibited signi®cant changes in chemical shift and decreases in the overall T 2 relaxation times in the presence of E1p, the residues principally affected being restricted to the half of the domain that contains the lipoyl-lysine (Lys41) residue. In addition, small chemical shift changes and a general drop in T 2 times in the presence of E1o were observed, indicating that E2plip holo can interact, weakly but non-productively, with E1o. It is evident that recognition of the protein domain is the ultimate determinant of whether reductive acetylation of the lipoyl group occurs, and that this is ensured by a mosaic of interactions with the Elp.

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

Cited by 76 publications

References 32 publications

Prediction of the Immunodominant Epitope of the Pyruvate Dehydrogenase Complex E2 in Primary Biliary Cirrhosis Using Phage Display

Prediction of the Immunodominant Epitope of the Pyruvate Dehydrogenase Complex E2 in Primary Biliary Cirrhosis Using Phage Display

Autoantibodies in primary sclerosing cholangitis

Recognition of the lipoyl domain is the ultimate determinant of substrate channelling in the pyruvate dehydrogenase multienzyme complex

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