Search

Abstract Background The mechanism underlying autoimmune diabetes has been difficult to define. There is a strong genetic contribution and numerous studies associate the major histocompatibility complex, especially the class II region, with predisposition or resistance. However, how these molecules are implicated remains obscure. Presentation of the hypothesis We have supplemented structural analysis with computational biophysical and sequence analyses and propose an heuristic for distinguishing between human leukocyte antigen molecules that predispose to insulin dependent diabetes mellitus and those that are protective. Polar residues at both β37 and β9 suffice to distinguish accurately between class II alleles that predispose to type 1 diabetes and those that do not. The electrostatic potential within the peptide binding pocket exerts a strong influence on diabetogenic epitopes with basic residues. Diabetes susceptibility alleles are predicted to bind autoantigens strongly with tight affinity, prolonged association and altered cytokine expression profile. Protective alleles bind moderately, and neutral alleles poorly or not at all. Non-Asp β57 is a modifier that supplements disease risk but only in the presence of the polymorphic, polar pair at β9 and β37. The nature of β37 determines resistance on one hand, and susceptibility or dominant protection on the other. Conclusion The proposed ideas are illustrated with structural, functional and population studies from the literature. The hypothesis, in turn, rationalizes their results. A plausible mechanism of immune mediated diabetes based on binding affinity and peptide kinetics is discussed. The number of the polymorphic markers present correlates with onset of disease and severity. The molecular elucidation of disease susceptibility and resistance paves the way for risk prediction, treatment and prevention of disease based on analogue peptides. Reviewers This article was reviewed by Eugene V. Koonin, Michael Lenardo, Hossam Ashour, and Bhagirath Singh. For the full reviews, please go to the Reviewers' comments section.

The adaptor protein ankyrin-R interacts via its membrane binding domain with the cytoplasmic domain of the anion exchange protein (AE1) and via its spectrin binding domain with the spectrin-based membrane skeleton in human erythrocytes. This set of interactions provides a bridge between the lipid bilayer and the membrane skeleton, thereby stabilizing the membrane. Crystal structures for the dimeric cytoplasmic domain of AE1 (cdb3) and for a 12-ankyrin repeat segment (repeats 13-24) from the membrane binding domain of ankyrin-R (AnkD34) have been reported. However, structural data on how these proteins assemble to form a stable complex have not been reported. In the current studies, site-directed spin labeling, in combination with electron paramagnetic resonance (EPR) and double electron-electron resonance, has been utilized to map the binding interfaces of the two proteins in the complex and to obtain inter-protein distance constraints. These data have been utilized to construct a family of structural models that are consistent with the full range of experimental data. These models indicate that an extensive area on the peripheral domain of cdb3 binds to ankyrin repeats 18-20 on the top loop surface of AnkD34 primarily through hydrophobic interactions. This is a previously uncharacterized surface for binding of cdb3 to AnkD34. Because a second dimer of cdb3 is known to bind to ankyrin repeats 7-12 of the membrane binding domain of ankyrin-R, the current models have significant implications regarding the structural nature of a tetrameric form of AE1 that is hypothesized to be involved in binding to full-length ankyrin-R in the erythrocyte membrane. [ABSTRACT FROM AUTHOR]

Competing Interests: None to declare.