Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically different amyloid fibrils.
Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically different amyloid fibrils.
复制标题
与家族性克雅氏病中淀粉样蛋白基因的不同突变区域相对应的合成肽显示出形态不同的淀粉样蛋白原纤维的体外形成增强。
DOI：
10.1073/pnas.90.10.4451
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发表时间：
1993
影响因子：
11.1
通讯作者：
Gajdusek,DC
中科院分区：
文献类型：
--
作者：
Goldfarb,LG;Brown,P;Haltia,M;Ghiso,J;Frangione,B;Gajdusek,DC
我们合成了与20号染色体淀粉样蛋白基因的密码子178（Asp-->Asn）和密码子200（Glu-->Lys）区域中正常和突变等位基因编码的序列相对应的多肽，这些基因与家族性克雅氏病有关。来自两个区域的肽悬浮液自发形成具有不同形态特征和聚集倾向的淀粉样原纤维。突变体中的纤维状阵列比正常肽悬浮液中的纤维状阵列更密集且更丰富，并且当同源突变体和正常肽混合在一起时甚至更加明显。在所有情况下，密码子 200 区域的制剂比密码子 178 区域的相应肽更容易形成纤维。这些体外观察结果支持这样的假设：克雅氏病致病性单等位基因点突变引起的氨基酸变化可能使正常宿主蛋白的体内折叠行为成核，从而有利于不溶性淀粉样原纤维的形成。
We synthesized polypeptides corresponding to sequences encoded by normal and mutant alleles in the regions of codon 178 (Asp-->Asn) and codon 200 (Glu-->Lys) of the chromosome 20 amyloid gene that have been linked to familial Creutzfeldt-Jakob disease. Peptide suspensions from both regions spontaneously formed amyloid fibrils with different morphological characteristics and aggregation tendencies. Fibrillar arrays were denser and more profuse in mutant than in normal peptide suspensions and were even more marked when the homologous mutant and normal peptides were mixed together. Preparations from the region of codon 200 were in all cases more fibrillogenic than corresponding peptides from the region of codon 178. These in vitro observations support the hypothesis that amino acid changes from pathogenic single-allele point mutations in Creutzfeldt-Jakob disease may nucleate the in vivo folding behavior of the normal host protein to favor formation of insoluble amyloid fibrils.