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J. Biol. Chem., Vol. 276, Issue 2, 1626-1633, January 12, 2001
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From the In primary (light chain-associated) amyloidosis,
immunoglobulin light chains deposit as amyloid fibrils in vital organs,
especially the kidney. Because the kidney contains high concentrations
of urea that can destabilize light chains as well as solutes such as
betaine and sorbitol that serve as protein stabilizers, we investigated
the effects of these solutes on in vitro amyloid fibril
formation and thermodynamic stability of light chains. Two recombinant
light chain proteins, one amyloidogenic and the other nonamyloidogenic,
were used as models. For both light chains, urea enhanced fibril
formation by reducing the nucleation lag time and diminished protein
thermodynamic stability. Conversely, betaine or sorbitol increased
thermodynamic stability of the proteins and partially inhibited fibril
formation. These solutes also counteracted urea-induced reduction in
protein thermodynamic stability and accelerated fibril formation.
Betaine was more effective than sorbitol. A model is presented to
explain how the thermodynamic effects of the solutes on protein state
equilibria can alter nucleation lag time and, hence, fibril formation
kinetics. Our results provide evidence that renal solutes control
thermodynamic and kinetic stability of light chains and thus may
modulate amyloid fibril formation in the kidney.
Counteracting Effects of Renal Solutes on Amyloid Fibril
Formation by Immunoglobulin Light Chains*
,,
**, and
Department of Pharmaceutical Sciences,
School of Pharmacy, University of Colorado Health Science Center,
Denver, Colorado 80262, § Department of Chemical
Engineering, University of Colorado, Boulder, Colorado 80309, ¶ Biosciences Division, Argonne National Laboratory,
Argonne, Illinois 60439, and Human Immunology and Cancer
Program, University of Tennessee Graduate School of Medicine,
Knoxville, Tennessee 37920
*
This work was supported by National Science Foundation Grant
BES 9816975 (to J. F. C. and T. W. R.) and United States Public Health Service Grant CA10050 (National Institutes of Health (NCI) (to
A. S.)).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 303-315-6075;
Fax: 303-315-6281; E-mail: John.Carpenter@uchsc.edu.
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