title: Effects of oxidative post-translational modifications on structural stability and self-assembly of λ6 immunoglobulin light chain.
abstract: 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.
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada; Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Canada.
authors.forename: Ximena
authors.initials: X
authors.lastname: Zottig
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada; Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laporte Wolwertz
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada.
authors.forename: Makan
authors.initials: M
authors.lastname: Golizeh
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: Ohlund
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada.
authors.forename: Lekha
authors.initials: L
authors.lastname: Sleno
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC H3C 3P8, Canada; Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Canada. Electronic address: bourgault.steve@uqam.ca.
authors.forename: Steve
authors.initials: S
authors.lastname: Bourgault
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000686:Amyloidosis / Q000209:etiology; D002460:Cell Line; D004926:Escherichia coli / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000235:genetics; D008297:Male; D015394:Molecular Structure; D009566:Nitrates / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D066329:Protein Aggregates; D050050:Protein Carbonylation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability
chemical_list: D000682:Amyloid; D007147:Immunoglobulin Light Chains; D009566:Nitrates; D066329:Protein Aggregates
keywords: Aggregation; Amyloid; Immunoglobulin; Light chain amyloidosis; Oxidative stress; Post-translational modifications