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Probing the role of λ6 immunoglobulin light chain dimerization in amyloid formation.
Wolwertz, Mathieu Laporte; Nguyen, Phuong Trang; Quittot, Noé; Bourgault, Steve.
Afiliación
  • Wolwertz ML; 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.
  • Nguyen PT; 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.
  • Quittot N; 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.
  • Bourgault S; 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.
Biochim Biophys Acta ; 1864(4): 409-18, 2016 Apr.
Article en En | MEDLINE | ID: mdl-26802902
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cadenas lambda de Inmunoglobulina / Multimerización de Proteína / Amiloide Idioma: En Revista: Biochim Biophys Acta Año: 2016 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cadenas lambda de Inmunoglobulina / Multimerización de Proteína / Amiloide Idioma: En Revista: Biochim Biophys Acta Año: 2016 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Países Bajos