Abstact

Accumulation of misfolded proteins is a hallmark of many neurodegenerative diseases. To characterize such misfolded species in vivo, conformation-specific antibodies are widely used; however, limited knowledge of antibody-epitope interactions often hampers mechanistic insight. To address this, we determined the cryo-electron microscopy structure of the complex between a monoclonal antibody, 19A9, and Cu/Zn-superoxide dismutase (SOD1), a protein associated with canine degenerative myelopathy (DM), which is related to human amyotrophic lateral sclerosis. Biochemical analyses confirmed that 19A9 specifically recognizes monomeric SOD1, and the structure revealed binding near the interface normally used for homodimerization in native SOD1, with steric hindrance preventing interaction when the protein is in its homodimeric form. Immunofluorescence staining of spinal cord sections revealed that 19A9 stained a subset of motoneurons in DM-affected dogs, but not in asymptomatic controls. Structural characterization of the 19A9-monomeric SOD1 complex enabled us to propose that SOD1 monomers can arise in vivo under pathological conditions.