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A structural basis for CD8(+) T cell-dependent recognition of non-homologous peptide ligands - Implications for molecular mimicry in autoreactivity
KTH, School of Biotechnology (BIO), Gene Technology.
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2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 29, 27069-27075 p.Article in journal (Refereed) Published
Abstract [en]

Molecular mimicry of self-epitopes by viral antigens is one possible pathogenic mechanism underlying induction of autoimmunity. A self-epitope, mDBM, derived from mouse dopamine beta-mono-oxygenase (KALYDYAPI) sharing 44% sequence identity with the lymphocytic choriomeningitis virus-derived immunodominant epitope gp33 (KAVYNFATC/ M), has previously been identified as a cross-reactive self-ligand, presentation of which results in autoimmunity. A rat peptide homologue, rDBM (KALYNYAPI, 56% identity to gp33), which displayed similar properties to mDBM, has also been identified. We herein report the crystal structure of H-2D(b)center dot rDBM and a comparison with the crystal structures of the cross-reactive H-2D(b)center dot gp33 and non- cross- reactive H-2D(b)center dot gp33 (V3L) escape variant (KALYNFATM, 88% identity to gp33). Despite the large sequence disparity, rDBM and gp33 peptides are presented in nearly identical manners by H-2D(b), with a striking juxtaposition of the central sections of both peptides from residues p3 to p7. The structural similarity provides H-2D(b) in complex with either a virus-derived or a dopamine beta-mono-oxygenase-derived peptide with a shared antigenic identity that conserves the positioning of the heavy chain and peptide residues that interact with the T cell receptor (TCR). This stands in contrast to the structure of H-2D(b) center dot gp33 (V3L), in which a single conserved mutation, also present in rDBM, induces large movements of both the peptide backbone and the side chains that interact with the TCR. The TCR-interacting surfaces of the H-2D(b) center dot rDBM and H-2D(b) center dot gp33 major histocompatibility complexes are very similar with regard to shape, topology, and charge distribution, providing a structural basis for CD8 T cell activation by molecular mimicry and potential subsequent development of autoreactivity.

Place, publisher, year, edition, pages
2005. Vol. 280, no 29, 27069-27075 p.
Keyword [en]
lymphocytic choriomeningitis virus, induced autoimmune-disease, class-ii molecule, self-peptides, antigen recognition, crystal-structures, sequence homology, cross-reactivity, escape mutants, viral peptides
URN: urn:nbn:se:kth:diva-14917ISI: 000230589500053OAI: diva2:332958
QC 20100525Available from: 2010-08-05 Created: 2010-08-05Bibliographically approved

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Odeberg, Jacob
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