title: Probing the role of λ6 immunoglobulin light chain dimerization in amyloid formation.
abstract: Light chain amyloidosis (AL) is a lethal disease associated with the deposition of misfolded immunoglobulin light chains (LC) as amyloid fibrils in the extracellular space of vital organs. The exact mechanisms of LC self-assembly and the molecular basis leading to cellular and organ failure still remain poorly understood. In this study, we investigated the relationship between the quaternary structure, the stability and the amyloidogenecity of LC variable domain (VL) from the λ6 germline. We observed that the amyloidogenic λ6 Wil and its non-amyloidogenic counterpart Jto dimerize in a concentration-dependent manner and that the dimer affinity is considerably decreased in the presence of a high ionic strength. Our results showed that the dimeric state delays the structural conversion associated with amyloid formation and that the monomer is critical to initiate amyloidogenesis. Thermal and chemical unfolding studies revealed that the dimeric state of VL λ6 has an equivalent stability to the monomer. This indicates that the protective effect of dimerization is not related to thermodynamic stability but, most likely, resides in specific structural features. The toxicity of monomeric Jto and Wil as well as fibrillar aggregates was evaluated on cardiomyoblasts and ThT-negative proteospecies reduced cellular viability when employed at high concentration. This study provides novel insights into the complex process of LC amyloidogenesis and suggests that dimer stabilization constitutes a promising strategy to prevent self-assembly and amyloid deposition.
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC, Canada, H3C 3P8; Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Canada.
authors.forename: Mathieu Laporte
authors.initials: ML
authors.lastname: Wolwertz
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC, Canada, H3C 3P8; Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Canada.
authors.forename: Phuong Trang
authors.initials: PT
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC, Canada, H3C 3P8; Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Canada.
authors.forename: Noé
authors.initials: N
authors.lastname: Quittot
authors.affiliation: Department of Chemistry, Pharmaqam, University of Québec in Montreal, Montreal, QC, Canada, H3C 3P8; 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 / Q000096:biosynthesis*; D007146:Immunoglobulin lambda-Chains / Q000737:chemistry*; D009994:Osmolar Concentration; D066329:Protein Aggregates; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D007146:Immunoglobulin lambda-Chains; D066329:Protein Aggregates
keywords: Aggregation; Amyloid; Dimerization; Immunoglobulin; Lambda germline; Light chain amyloidosis