Long charge-rich alpha-helices in systemic autoantigens

Autoimmune diseases are characterized by the presence of antibodies and T-cells targeting restricted sets of host proteins. This phenomenon may be due in part to greater non-specific immunogenicity for these proteins compared to others which are not autoantigenic. We used computer-based methods to analyze the sequenced human autoantigens for distinctive patterns of potential immunologic importance. Sequences longer than 27 residues predicted by these methods to form coiled-coil alpha-helices with a probability greater than 0.9 were detected in 40 of 109 (36.7%) of the known human autoantigens. These include many predominantly systemic disease-specific autoantigens not previously known to contain this structure. In comparison, 8.7% of human proteins in the Swissprot data base, and 1.1% of the proteins in the Brookhaven data base were found to contain such segments. These predicted coiled-coil alpha-helices are distinguished from most globular protein helices by greater length, higher charge content, and a heptad repeat multivalency. Coiled-coil segments correlate in part with known autoantibody epitopes and may contribute to autoantigenic potential. Systemic autoantigens generally are either basic or contain extended, multivalent, charge-rich segments such as coiled-coils.