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The Structural Determinants of the Immunoglobulin Light Chain Amyloid Aggregation

  • Luis Del Pozo-YaunerEmail author
  • Baltazar Becerril
  • Adrián Ochoa-Leyva
  • Sandra Leticia Rodríguez-Ambriz
  • Julio Isael Pérez Carrión
  • Guadalupe Zavala-Padilla
  • Rosana Sánchez-López
  • Daniel Alejandro Fernández Velasco

Abstract

The extracellular deposition of a monoclonal immunoglobulin light chain (LC) as insoluble fibrillar aggregates is the cause of the primary systemic amyloidosis, also known as light chain-derived (AL) amyloidosis. In this chapter the structural factors determining the potential of the LC to aggregate into amyloid fibrils are analyzed. In the first two sections, the relationship between protein aggregation and disease, as well as the causes and characteristics of the human amyloidoses are discussed. The role of protein misfolding in the fibril assembly pathway and the structural bases of the amyloid fibrils stability are also addressed. Then, the chapter focuses on the molecular causes of the amyloid aggregation of LC. The contribution of the somatic mutations and the identity of the variable gene segment encoding the LC to the propensity to form amyloid fibrils are discussed. The chapter summarizes the experimental evidence supporting the role of partially folded intermediates in the mechanism of AL fibril assembly, as well as the modulatory effect played by the variable region gene sequence on the aggregation behavior of the LC. Finally, the results of a recent study aimed to identify fibrillogenic regions in the λ6 recombinant variable domain protein 6aJL2 are presented.

Keywords

Misfolding disease Amyloidosis Amyloid fibril Protein misfolding Non-native intermediate Protein aggregation Immunoglobulin light chain Lambda 6 subgroup Fibrillogenesis Profibrillogenic sequence 

Notes

Acknowledgment

This work was supported in part by grants from the Consejo Nacional de Ciencia y Tecnología (No. 169659) to L. del Pozo-Yauner.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Luis Del Pozo-Yauner
    • 1
    Email author
  • Baltazar Becerril
    • 2
  • Adrián Ochoa-Leyva
    • 1
  • Sandra Leticia Rodríguez-Ambriz
    • 3
  • Julio Isael Pérez Carrión
    • 1
  • Guadalupe Zavala-Padilla
    • 2
  • Rosana Sánchez-López
    • 2
  • Daniel Alejandro Fernández Velasco
    • 4
  1. 1.Laboratorio de Estructura de ProteínasInstituto Nacional de Medicina GenómicaTlalpan, MéxicoMexico
  2. 2.Instituto de Biotecnología UNAMCuernavacaMexico
  3. 3.Centro de Desarrollo de Productos Bióticos, IPNYautepecMexico
  4. 4.Facultad de Medicina UNAMMéxicoMexico

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