Counteracting effects of renal solutes on amyloid fibril formation by immunoglobulin light chains.
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.
Kim
Y S
YS
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Science Center, Denver, Colorado 80262, USA.
Cape
S P
SP
Chi
E
E
Raffen
R
R
Wilkins-Stevens
P
P
Stevens
F J
FJ
Manning
M C
MC
Randolph
T W
TW
Solomon
A
A
Carpenter
J F
JF
D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D000686:Amyloidosis / Q000235:genetics / Q000276:immunology*; D001622:Betaine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics; D007668:Kidney / Q000503:physiopathology*; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology; D013012:Sorbitol / Q000494:pharmacology; D013816:Thermodynamics; D014508:Urea / Q000494:pharmacology* / Q000652:urine
D000682:Amyloid; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D001622:Betaine; D013012:Sorbitol; D014508:Urea; D019791:Guanidine