Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients.

Abstract

It is now accepted that the ability of a protein to form amyloid fibrils could be associated both kinetic and thermodynamic protein folding parameters. A recent study from our laboratory using recombinant full-length (encompassing the variable and constant domain) immunoglobulin light chains found a strong kinetic control of the protein unfolding for these proteins. In this study, we are extending our analysis by using urine-derived Bence Jones proteins (BJPs) from five patients with light chain (AL) amyloidosis and four patients with multiple myeloma (MM). We observed lower stability in κ proteins compared to λ proteins (for both MM and AL proteins) in agreement with previous studies. The kinetic component of protein stability is not a universal feature of BJPs and the hysteresis observed during refolding reactions could be attributed to the inability of the protein to refold all domains. The most stable proteins exhibited 3-state unfolding transitions. While these proteins do not refold reversibly, partial refolding shows 2-state partial refolding transitions, suggesting that one of the domains (possibly the variable domain) does not refold completely. Sequences were aligned with their respective germlines and the location and nature of the mutations were analyzed. The location of the mutations were analyzed and compared with the stability and amyloidogenic properties for the proteins in this study, increasing our understanding of light chain unfolding and amyloidogenic potential.

• Authors: Luis M Blancas-Mejía, Emily B Martin, Angela Williams, Jonathan S Wall, Marina Ramirez-Alvarado
• Journal: Biophysical chemistry (Biophys Chem) Vol. 230 Pg. 89-98 (11 2017) ISSN: 1873-4200 [Electronic] Netherlands
• PMID: 28916410 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Bence Jones Protein

Topics

• Amino Acid Sequence
• Amyloidosis (metabolism, pathology)
• Bence Jones Protein (chemistry, metabolism, urine)
• Circular Dichroism
• Humans
• Immunoglobulin Light-chain Amyloidosis
• Kinetics
• Multiple Myeloma (metabolism, pathology)
• Protein Folding
• Protein Stability
• Protein Structure, Secondary
• Protein Structure, Tertiary
• Protein Unfolding
• Sequence Alignment
• Temperature