Basis of the IgM cleavage activity of IgMDE_Lsp and IgMDE_Mma

Abnormally elevated immunoglobulin M (IgM) levels can cause tissue damage and increase susceptibility to bacterial infections. Therefore, the use of IgM-degrading enzymes is clinically important for treating diseases characterized by elevated IgM levels. IgMDE_Lsp and IgMDE_Mma are two newly discovered highly specific IgM-degrading enzymes. Here, we resolved the crystal structures of IgMDE_Lsp and IgMDE_Mma. Despite their highly conserved structure, the activity level of IgMDE_Lsp is significantly greater than that of IgMDE_Mma. By predicting their complexes with the IgM substrate, we deduced the potential reasons for their substantial activity disparity. IgMDE_Lsp exhibits high IgM-cleaving activity through triplet catalysis. We inferred the potential reasons for their vastly differing activities by predicting their complexes with the IgM substrate. IgMDE_Lsp exhibits high IgM cleavage activity through its catalytic triad. However, IgMDE_Mma exists in multiple polymeric states, particularly dimers, in which spatial steric effects arise during substrate recognition. These dimers interfere with IgM Fc through spatial conflicts, partially hindering binding and IgM cleavage via the catalytic triad, which likely underlies its significantly lower activity than IgMDE_Lsp. We subsequently validated the in vivo activity of IgMDE_Lsp in mice. Overall, the structural elucidation of these novel IgM-degrading enzymes provides potential therapeutic targets for diseases characterized by elevated IgM levels.