Thermodynamic modulation of light chain amyloid fibril formation

Yong Sung Kim, Jonathan Wall, Jeffrey Meyer, Charles Murphy, Theodore W. Randolph, Mark C. Manning, Alan Solomon, John F. Carpenter

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

To obtain further insight into the pathogenesis of amyloidosis and develop therapeutic strategies to inhibit fibril formation we investigated: 1) the relationship between intrinsic physical properties (thermodynamic stability and hydrogen-deuterium (H-D) exchange rates) and the propensity of human immunoglobulin light chains to form amyloid fibrils in vitro; and 2) the effects of extrinsically modulating these properties on fibril formation. An amyloid-associated protein readily formed amyloid fibrils in vitro and had a lower free energy of unfolding than a homologous nonpathological protein, which did not form fibrils in vitro. H-D exchange was much faster for the pathological protein, suggesting it had a greater fraction of partially folded molecules. The thermodynamic stabilizer sucrose completely inhibited fibril formation by the pathological protein and shifted the values for its physical parameters to those measured for the nonpathological protein in buffer alone. Conversely, urea sufficiently destabilized the nonpathological protein such that its measured physical properties were equivalent to those of the pathological protein in buffer, and it formed fibrils. Thus, fibril formation by light chains is predominantly controlled by thermodynamic stability; and a rational strategy to inhibit amyloidosis is to design high affinity ligands that specifically increase the stability of the native protein.

Original languageEnglish (US)
Pages (from-to)1570-1574
Number of pages5
JournalJournal of Biological Chemistry
Volume275
Issue number3
DOIs
StatePublished - Jan 21 2000

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Thermodynamics
Amyloid
Modulation
Light
Proteins
Deuterium
Amyloidosis
Hydrogen
Buffers
Immunoglobulin Light Chains
Amyloidogenic Proteins
Thermodynamic stability
Physical properties
Protein Stability
Sucrose
Urea
Free energy
Ligands
Molecules
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kim, Y. S., Wall, J., Meyer, J., Murphy, C., Randolph, T. W., Manning, M. C., ... Carpenter, J. F. (2000). Thermodynamic modulation of light chain amyloid fibril formation. Journal of Biological Chemistry, 275(3), 1570-1574. https://doi.org/10.1074/jbc.275.3.1570

Thermodynamic modulation of light chain amyloid fibril formation. / Kim, Yong Sung; Wall, Jonathan; Meyer, Jeffrey; Murphy, Charles; Randolph, Theodore W.; Manning, Mark C.; Solomon, Alan; Carpenter, John F.

In: Journal of Biological Chemistry, Vol. 275, No. 3, 21.01.2000, p. 1570-1574.

Research output: Contribution to journalArticle

Kim, YS, Wall, J, Meyer, J, Murphy, C, Randolph, TW, Manning, MC, Solomon, A & Carpenter, JF 2000, 'Thermodynamic modulation of light chain amyloid fibril formation', Journal of Biological Chemistry, vol. 275, no. 3, pp. 1570-1574. https://doi.org/10.1074/jbc.275.3.1570
Kim, Yong Sung ; Wall, Jonathan ; Meyer, Jeffrey ; Murphy, Charles ; Randolph, Theodore W. ; Manning, Mark C. ; Solomon, Alan ; Carpenter, John F. / Thermodynamic modulation of light chain amyloid fibril formation. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 3. pp. 1570-1574.
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