Goldfarb L G, Brown P, Haltia M, Ghiso J, Frangione B, Gajdusek D C
Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1993 May 15;90(10):4451-4. doi: 10.1073/pnas.90.10.4451.
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.
我们合成了与20号染色体淀粉样蛋白基因密码子178（天冬氨酸→天冬酰胺）和密码子200（谷氨酸→赖氨酸）区域中正常和突变等位基因编码序列相对应的多肽，这些区域已与家族性克雅氏病相关联。来自这两个区域的肽悬浮液自发形成了具有不同形态特征和聚集倾向的淀粉样纤维。与正常肽悬浮液相比，突变肽悬浮液中的纤维状阵列更密集、更丰富，当同源突变肽和正常肽混合在一起时，这种现象更为明显。在所有情况下，来自密码子200区域的制剂比来自密码子178区域的相应肽更易形成纤维。这些体外观察结果支持以下假设：克雅氏病中致病性单等位基因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，从而有利于形成不溶性淀粉样纤维。
