Fig. 8

A disulfide shuffling mechanism describes exposure of pathological epitope in SOD1. (a) Schematic representation of the epitopes of the antibodies that exclusively detect the pathological inclusions in SOD1-ALS cases. (b) The regions of the overlapped epitopes among antibodies specific to pathological SOD1 (Gly 44 - Asn 53, green; Asn 131 - Ile 151, purple) are mapped on the crystal structure of the native SOD1 protein (PDB ID: 2C9V). Together with the intramolecular disulfide bond (Cys 57 - Cys 146) in yellow, copper and zinc ions are also shown as blue and red ball models, respectively. (c) Schematic representation of the epitope exposure through the disulfide shuffling mechanism. Cys 57 and 146, which form the canonical disulfide bond, are shown as “S” in yellow, while the other two free Cys residues, Cys 6 and 111, as S in green. Red curves represent loops IV and VII. Mutation-induced conformational disorder of SOD1 allows the free Cys (green S) to nucleophilically attack and then shuffle the Cys 57 - Cys 146 disulfide bond (yellow). The disulfide shuffling within and between SOD1 molecules is considered to peel the loops (red) off from the structural core of SOD1 and thereby expose the epitope (arrows in red) for our antibodies