Figure 13.

The crystal structure of the α345 hexamer reveals common “hotspots” of bioactivity, where pathogenic mechanisms converge. The Z-appendage and the GP hypoepitopes are located at the same sites of α3 and α5 subunits near the apices of the α345 hexamer which are called loop-crevice-loop (LCL) bioactive sites (α4 LCL site located on back side of the hexamer). This indicates that the pathogenic mechanisms of GP and AS converge at these sites, thus revealing “hotspots” of bioactivity. In Alport syndrome, a number of pathogenic variants including the Zurich variant are located within the LCL sites (top left). In addition, there are numerous other hypomorph variants on the surface that can affect LCL function (see Figs. S12–S14). In familial GP disease, the Zurich variant within the LCL sites could predispose the site for a trigger of autoantibody production (top right). In sporadic GP, the same LCL site is vulnerable to endogenous and exogenous triggers that elicit the immune response. Similarly, in diabetic nephropathy, this site is vulnerable to hyperglycemia-derived modifications of Lys and Arg residues at the hexamer surface. These modifications are in fact equivalent to genetic variants that cause structural perturbation and dysfunction. They can cause GBM thickening, a hallmark feature of diabetic nephropathy (35). AS, Alport syndrome; GBM, glomerular basement membrane; GP, Goodpasture’s disease.