Decreased thermodynamic stability as a crucial factor for familial amyloidotic polyneuropathy.
A single mutation in the wild-type transthyretin (WT TTR) such as V30M causes a familial amyloidotic polyneuropathy disease. Comparison of the three-dimensional crystal structures of WT and V30M does not tell much about the reason. High-pressure NMR revealed that at neutral pH both WT and V30M exist as equilibrium between the native tetramer and the dissociated/unfolded monomer. The native tetramer is highly stable in WT (deltaG(0)=104 kJ/mol at 37 degrees C, pH 7.1), but the stability is significantly reduced in V30M (deltadeltaG(0)=-18 kJ/mol), increasing the fraction of the unfolded monomer by a 1000-fold. Significant reduction of thermodynamic stability of WT TTR by mutation could be a crucial factor for familial amyloidotic polyneuropathy.
Niraula
Tara Nath
TN
Graduate School of Science and Technology, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
Haraoka
Katsuki
K
Ando
Yukio
Y
Li
Hua
H
Yamada
Hiroaki
H
Akasaka
Kazuyuki
K
D028227:Amyloid Neuropathies, Familial / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004058:Diffusion; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics; D011312:Pressure; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics
D011228:Prealbumin