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Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.

ABSTRACT: AIM:To approach the elusive function of the SLA/LP molecule, we have characterized genomic organization and conservation of the major antigenic and functional properties of the SLA/LP molecule in various species. METHODS:By means of computational biology, we have characterized the complete SLA/LP gene, mRNA and deduced protein sequences in man, mouse, zebrafish, fly, and worm. RESULTS:The human SLA/LP gene sequence of approximately 39 kb, which maps to chromosome 4p15.2, is organized in 11 exons, of which 10 or 11 are translated, depending on the splice variant. Homologous molecules were identified in several biological model organisms. The various homologous protein sequences showed a high degree of similarity or homology, notably at those residues that are of functional importance. The only domain of the human protein sequence that lacks significant homology with homologous sequences is the major antigenic epitope recognized by autoantibodies from autoimmune hepatitis (AIH) patients. CONCLUSION:The SLA/LP molecule and its functionally relevant residues have been highly conserved throughout the evolution, suggesting an indispensable function of the molecule. The finding that the only non-conserved domain is the dominant antigenic epitope of the human SLA/LP sequence, suggests that SLA/LP autoimmunity is autoantigen-driven rather than being driven by molecular mimicry.

SUBMITTER: Wang CX

PROVIDER: S-EPMC4066155 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.

Wang Chun-Xia CX Teufel Andreas A Cheruti Uta U Grötzinger Joachim J Galle Peter R PR Lohse Ansgar W AW Herkel Johannes J

World journal of gastroenterology 20060201 6

<h4>Aim</h4>To approach the elusive function of the SLA/LP molecule, we have characterized genomic organization and conservation of the major antigenic and functional properties of the SLA/LP molecule in various species.<h4>Methods</h4>By means of computational biology, we have characterized the complete SLA/LP gene, mRNA and deduced protein sequences in man, mouse, zebrafish, fly, and worm.<h4>Results</h4>The human SLA/LP gene sequence of approximately 39 kb, which maps to chromosome 4p15.2, is ...[more]

PMID: 16521218

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Project description:BACKGROUND:Autoimmune hepatitis (AIH) is a chronic, progressive liver disease, characterized by continuing hepatocellular inflammation and necrosis. A subgroup of AIH patients presents specific autoantibodies to soluble liver antigen/liver-pancreas (SLA/LP) protein, which is regarded as a highly specific diagnostic marker. Autoantigenic SLA/LP peptides are targeted by CD4+ T cells, and restricted by the allele HLA-DRB1*03:01, which confers disease susceptibility in Europeans and Americans. A positively charged residue at position 71 has been indicated as critical for AIH susceptibility in all of the HLA alleles identified to date. Though the exact molecular mechanisms underlying pathogenesis of AIH are not clear, molecular mimicry between SLA/LP and viral/bacterial antigens has been invoked. METHODS:The immunodominant region of SLA/LP was used as query in databank searches to identify statistically significant similarities with viral/bacterial peptides. Homology modeling and docking was used to investigate the potential interaction of HLA-DRB1*03:01 with the identified peptides. By molecular mechanics means, the interactions and energy of binding at the HLA binding site was also scrutinized. RESULTS:A statistically significant structural similarity between the immunodominant regions of SLA/LP and a region of the surface antigen PS 120 from Rickettsia spp. has been detected. The interaction of the SLA/LP autoepitope and the corresponding Rickettsia sequence with the allele HLA-DRB1*03:01 has been simulated. The obtained results predict for both peptides a similar binding mode and affinity to HLA-DRB1*03:01. A "hot spot" of interaction between HLA-DRB1*03:01 and PS 120 is located at the P4 binding pocket, and is represented by a salt bridge involving Lys at position 71 of the HLA protein, and Glu 795 of PS120 peptide. CONCLUSIONS:These findings strongly support the notion that a molecular mimicry mechanism can trigger AIH onset. CD4+ T cells recognizing peptides of SLA/LP could indeed cross-react with foreign Rickettsia spp. antigens. Finally, the same analysis suggests a molecular explanation for the importance of position 71 in conferring the susceptibility of the allele HLA-DRB1*03:01 to AIH. The lack of a positive charge at such position could prevent HLA alleles from binding the foreign peptides and triggering the molecular mimicry event.

Dataset Information

Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.

Publications

Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.

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