Protein conformation and disease: Pathological consequences of analogous mutations in homologous proteins

The antibody light chain variable domain (V-L)(1) and myelin protein zero ( MPZ) are representatives of the functionally diverse immunoglobulin superfa mily. The V-L is a subunit Of the antigen-binding component of antibodies, while MPZ is the major membrane-linked constituent of the myelin sheaths th at coat peripheral nerves. Despite limited amino acid sequence homology, th e conformations of the core structures of the two proteins are largely supe rimposable. Amino acid variations in V-L account for various conformational disease outcomes, including amyloidosis. However, the specific amino acid changes in V-L that are responsible for disease have been obscured by multi ple concurrent primary structure alterations. Recently, certain demyelinati on disorders have been linked to point mutations and single amino acid poly morphisms in MPZ. We demonstrate here that some pathogenic variations in MP Z correspond to changes suspected of determining amyloidosis in V-L. This u nanticipated observation suggests that studies of the biophysical origin of conformational disease in one member of a superfamily of homologous protei ns may have implications throughout the superfamily. In some cases, finding s may account for overt disease; in other cases, due to the natural reperto ire of inherited polymorphisms, variations in a representative protein may predict subclinical impairment of homologous proteins.