Effects of oxidative post-translational modifications on structural stability and self-assembly of λ6 immunoglobulin light chain

- Immunoglobulin light chain assembly and amyloid deposition are associated with AL amyloidosis.
- Oxidative post-translational modifications were introduced to the λ6 light chain Wil.
- HNE-conjugation and nitration modulated the kinetics of aggregation.
- Tyr nitration decreased the thermodynamic stability of the protein.
- His-carbonylation altered the conformational conversion driving self-assembly.

Light chain amyloidosis (AL) originates from the deposition of immunoglobulin light chains (LCs) as amyloid fibrils in the extracellular space of vital organs. Although non-enzymatic post-translational modifications (PTMs) have been shown to contribute to protein misfolding diseases, little is known about their contributions to LC amyloidogenicity. In this study, we investigated the effects of three oxidative PTMs, carbonylation by hydroxynonenal (HNE), oxidation and nitration, on the structure, thermodynamic stability and self-assembly propensity of a LC variable domain from the λ6 germline, Wil. We initially identified the specific residues that are susceptible to oxidative chemical modifications. HNE-conjugation at specific His residues and nitration of Tyr side chains modulated the conformational conversion driving Wil self-assembly and fibrillar aggregates formation. This study reinforces the notion that not only the thermodynamic stability, but also the chemical and structural properties, should be considered when evaluating the amyloidogenic potential of a LC.