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

28 Citations (Scopus)

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
StatePublished - 1999
Externally publishedYes

Fingerprint

Bence Jones Protein
Amyloidosis
Proteins
Pericardium
Isoelectric Point
Plasma Cells
Sepharose
Adipose Tissue
Chromatography
Immunoglobulins
Myocardium
Gels
Cell Proliferation
Urine
Light
Peptides

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Rostagno, A., Vidal, R., Kaplan, B., Chuba, J., Kumar, A., Elliott, J. I., ... Ghiso, J. (1999). pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein. British Journal of Haematology, 107(4), 835-843.

pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein. / Rostagno, Agueda; Vidal, Ruben; Kaplan, Batia; Chuba, Joseph; Kumar, Ashok; Elliott, James I.; Frangione, Blas; Gallo, Gloria; Ghiso, Jorge.

In: British Journal of Haematology, Vol. 107, No. 4, 1999, p. 835-843.

Research output: Contribution to journalArticle

Rostagno, A, Vidal, R, Kaplan, B, Chuba, J, Kumar, A, Elliott, JI, Frangione, B, Gallo, G & Ghiso, J 1999, 'pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein', British Journal of Haematology, vol. 107, no. 4, pp. 835-843.
Rostagno A, Vidal R, Kaplan B, Chuba J, Kumar A, Elliott JI et al. pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein. British Journal of Haematology. 1999;107(4):835-843.
Rostagno, Agueda ; Vidal, Ruben ; Kaplan, Batia ; Chuba, Joseph ; Kumar, Ashok ; Elliott, James I. ; Frangione, Blas ; Gallo, Gloria ; Ghiso, Jorge. / pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein. In: British Journal of Haematology. 1999 ; Vol. 107, No. 4. pp. 835-843.
@article{245057d789b3497fab3dbf2baede0553,
title = "pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein",
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.",
keywords = "κ light chain, AL amyloidosis, Amyloid fibrils, Bence Jones protein, Fibrillogenesis",
author = "Agueda Rostagno and Ruben Vidal and Batia Kaplan and Joseph Chuba and Ashok Kumar and Elliott, {James I.} and Blas Frangione and Gloria Gallo and Jorge Ghiso",
year = "1999",
language = "English (US)",
volume = "107",
pages = "835--843",
journal = "British Journal of Haematology",
issn = "0007-1048",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - pH-Dependent fibrillogenesis of a V(κ)III Bence Jones protein

AU - Rostagno, Agueda

AU - Vidal, Ruben

AU - Kaplan, Batia

AU - Chuba, Joseph

AU - Kumar, Ashok

AU - Elliott, James I.

AU - Frangione, Blas

AU - Gallo, Gloria

AU - Ghiso, Jorge

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

KW - κ light chain

KW - AL amyloidosis

KW - Amyloid fibrils

KW - Bence Jones protein

KW - Fibrillogenesis

UR - http://www.scopus.com/inward/record.url?scp=0033386868&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033386868&partnerID=8YFLogxK

M3 - Article

C2 - 10606892

AN - SCOPUS:0033386868

VL - 107

SP - 835

EP - 843

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 4

ER -