Effect of nitric oxide in amyloid fibril formation on transthyretin-related amyloidosis.
Although oxidative stress is said to play an important role in the amyloid formation mechanism in several types of amyloidosis, few details about this role have been described. Amyloid is commonly deposited around the vessels that are the primary site of action of nitric oxide generated from endothelial cells and smooth muscle cells, so nitric oxide may be also implicated in amyloid formation. For this study, we examined the in vitro effect of S-nitrosylation on amyloid formation induced by wild-type transthyretin, a precursor protein of senile systemic amyloidosis, and amyloidogenic transthyretin V30M, a precursor protein of amyloid deposition in familial amyloidotic polyneuropathy. S-Nitrosylation of amyloidogenic transthyretin V30M via the cysteine at position 10 was 2 times more extensive than that of wild-type transthyretin in a nitric oxide-generating solution. Both wild-type transthyretin and amyloidogenic transthyretin V30M formed amyloid fibrils under acidic conditions, and S-nitrosylated transthyretins exhibited higher amyloidogenicity than did unmodified transthyretins. Moreover, S-nitrosylated amyloidogenic transthyretin V30M formed more fibrils than did S-nitrosylated wild-type transthyretin. Structural studies revealed that S-nitrosylation of amyloidogenic transthyretin V30M induced a change in its conformation, as well as instability of the tetramer conformation. These results suggest that the nitric oxide-mediated modification of transthyretin, especially variant transthyretin, may play an important role in amyloid formation in senile systemic amyloidosis and familial amyloidotic polyneuropathy.
Saito
Shiori
S
Department of Biopharmaceutics, Graduate School of Pharmaceutical Science, Kumamoto University, Kumamoto, Japan.
Ando
Yukio
Y
Nakamura
Masaaki
M
Ueda
Mitsuharu
M
Kim
Jaemi
J
Ishima
Yu
Y
Akaike
Takaaki
T
Otagiri
Masaki
M
D019943:Amino Acid Substitution / Q000235:genetics*; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D017354:Point Mutation; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D014633:Valine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D011228:Prealbumin; D009569:Nitric Oxide; D008715:Methionine; D014633:Valine