Mutational and genetic determinants of λ6 light chain amyloidogenesis

Authors

  • Martín González-Andrade,

    1. Consorcio Bioquímica de Enfermedades Crónicas, Instituto Nacional de Medicina Genómica (INMEGEN), México
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  • Baltazar Becerril-Luján,

    1. Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, México
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  • Rosana Sánchez-López,

    1. Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, México
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  • Héctor Ceceña-Álvarez,

    1. Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México
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  • Julio I. Pérez-Carreón,

    1. Consorcio Bioquímica de Enfermedades Crónicas, Instituto Nacional de Medicina Genómica (INMEGEN), México
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  • Ernesto Ortiz,

    1. Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, México
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  • D. Alejandro Fernández-Velasco,

    1. Laboratorio de Fisicoquímica e Ingeniería de Proteínas, Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México
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  • Luis del Pozo-Yauner

    Corresponding author
    1. Consorcio Bioquímica de Enfermedades Crónicas, Instituto Nacional de Medicina Genómica (INMEGEN), México
    • Correspondence

      L. del Pozo-Yauner, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, México, D.F., C.P. 14610, México

      Fax: +52 (55) 5350 1999

      Tel: +52 (55) 5350 1900

      E-mail: ldelpozo@inmegen.gob.mx

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Abstract

Approximately 25% of the λ6 light chains have glycine rather than arginine at position 25, which is an allelic variant of the IGLV6-57 (6a) locus. The Gly25 variant has been shown to decrease the folding stability of the germline λ6 VL protein 6aJL2 by 1.7 kcal·mol−1. In this work, we compared the thermodynamic and fibrillogenic properties of the amyloidosis (AL) derived recombinant (r) VL protein AR, which contains the allelic variant Gly25, with those of germline rVL 6aJL2-R25G and the λ6 disease-associated VL proteins Wil (AL) and Jto (myeloma). Our experiments show that of the four proteins AR is the least stable; forms amyloid fibrils at physiological temperature, pH and ionic strength; has the shortest lag time; and elongates homologous seeds most efficiently. We conclude that the Gly25 allelic variant, together with the somatic mutations, contributes importantly to the extremely low stability and high amyloidogenicity of the AL-derived protein AR.

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