pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein

Agueda Rostagno, Ruben Vidal, Batia Kaplan, Joseph Chuba, Ashok Kumar, James I. Elliott, Blas Frangione, Gloria Gallo, Jorge Ghiso

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Disorders of immunoglobulin (Ig) synthesis that occur in malignant plasma-cell proliferation may result in either granular (LCDD) or fibrillar (AL) tissue deposition of light-chain monoclonal components. The structural features that govern the transition from soluble polypeptides to either fibrillar or granular conformational states remain undefined. Among the many factors presumed to play a role in these transitions the net charge of the molecule has been associated with folding conformation changes. The majority of the proteins involved in AL amyloidosis show acidic isoelectric points (pI 3.8-5.2), whereas most L chains with basic pIs deposit in granular patterns. In our studies a 12 kD V(κ)III fragment was purified as the main component of the fibrils isolated from myocardium and adipose tissue of the pericardium obtained post-mortem from an individual with systemic AL amyloidosis. An apparently identical 12 kD VL fragment with the same N-terminal sequence constituted the BJ protein present in the urine. This urinary protein exhibited strikingly cathodic electrophoretic mobility on agarose gels and lacked retention by anionic exchange chromatography matrices, indicative of a highly basic pI (>10). When it was subjected to in vitro fibril-formation experiments, the BJ protein adopted a fibrillar conformation only at acidic pHs, remaining aggregated but not fibrillar at physiological pH. The data indicate that a specific tissue deposition pattern involves not only structural properties of the protein but rather more complex mechanisms in which acidic micro-environments may contribute to the stabilization of amyloidogenic conformations.

Original languageEnglish (US)
Pages (from-to)835-843
Number of pages9
JournalBritish journal of haematology
Volume107
Issue number4
DOIs
StatePublished - 1999

Keywords

  • AL amyloidosis
  • Amyloid fibrils
  • Bence Jones protein
  • Fibrillogenesis
  • κ light chain

ASJC Scopus subject areas

  • Hematology

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    Rostagno, A., Vidal, R., Kaplan, B., Chuba, J., Kumar, A., Elliott, J. I., Frangione, B., Gallo, G., & Ghiso, J. (1999). pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein. British journal of haematology, 107(4), 835-843. https://doi.org/10.1046/j.1365-2141.1999.01778.x