Structural Basis For The Crypticity Of B Cell Epitopes Of The Goodpasture Autoantigen: The Role Of Novel Collagen Iv Crosslinks

The autoantigens of certain autoimmune diseases harbor B cell epitopes that are sequestered by the antigen's tertiary or quaternary structure. The exposure of such cryptic epitopes, prompted by pathophysiological conditions, may be an important feature in the etiology of autoimmune disease. Here, we investigated the structural basis for the crypticity of B cell epitopes of the autoantigen of Goodpasture disease, an autoimmune disorder that causes rapidly progressive glomerulonephritis and pulmonary hemorrhage. The native autoantigen is the α3α4α5 noncollagenous hexamer, a globular domain that connects two triple‐helical protomers within the collagen IV network of basement membranes. The complete crypticity of autoepitopes within the hexamer correlates with the presence of dimer subunits. Here, the chemical basis for dimer formation was determined. Mass spectrometry analyses demonstrate that the α3α5‐heterodimers are connected by s‐hydroxylysyl‐methionine crosslinks, whereas, the α4α4‐homodimers are connected by s‐lysyl‐methionine crosslinks. These crosslinks function as molecular fasteners that reinforce the hexamers and block the accessibility of autoantibodies rendering the epitopes completely cryptic. Perturbation of the assembly or cleavage of crosslinks may be a key factor in the etiology of Goodpasture disease