TRUNCATED FORMS OF THE HUMAN PRION PROTEIN IN NORMAL BRAIN AND IN PRION DISEASES
TRUNCATED FORMS OF THE HUMAN PRION PROTEIN IN NORMAL BRAIN AND IN PRION DISEASES
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DOI：
10.1074/jbc.270.32.19173
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发表时间：
1995-08-11
影响因子：
4.8
通讯作者：
AUTILIOGAMBETTI, L
中科院分区：
文献类型：
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作者：
CHEN, SG;TEPLOW, DB;AUTILIOGAMBETTI, L
朊病毒蛋白（PrPc）的细胞形式是通过糖基磷脂酰肌醇部分锚定到细胞膜的糖蛋白。一种对蛋白酶部分耐药的异常形式PrPc，PrPres，是朊病毒疾病的标志，在人类中包括克雅氏病（CJD），Gerstmann-Straussler-Scheinker综合征和致命的家族性失眠症。我们的特点是在正常和病理人类大脑的主要形式的PrP。PrPc的COOH末端片段，命名为C1，在正常和CJD脑以及人神经母细胞瘤细胞中丰富。序列分析表明，C1含有从His-111或Met-112开始的替代NH 2末端。与PrPc一样，C1被糖基化，锚定在细胞膜上，并且是热稳定的。与PrPc的NH 2-末端区域的缺乏一致，C1比PrPc更酸性，并且不结合肝素。另外一个比C1长的片段，称为C2，在CJD大脑中大量存在。与PrPres一样，C2对蛋白酶具有抗性，并且不溶于洗涤剂。我们的数据表明，C1是正常的PrPc代谢的主要产物，产生的裂解，破坏了神经毒性和淀粉样蛋白的区域，包括残基106-126的PrP。该区域在C2中保持完整，表明C2在朊病毒疾病中的作用。
The cellular form of the prion protein (PrPc) is a glycoprotein anchored to the cell membrane by a glycosylphosphatidylinositol moiety. An aberrant form of PrPc that is partially resistant to proteases, PrPres, is a hallmark of prion diseases, which in humans include Creutzfeldt Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. We have characterized the major forms of PrP in normal and pathological human brains. A COOH-terminal fragment of PrPc, designated C1, is abundant in normal and CJD brains as well as in human neuroblastoma cells. Sequence analysis revealed that C1 contains alternative NH2 termini starting at His-111 or Met-112. Like PrPc, C1 is glycosylated, anchored to the cell membrane, and is heat stable. Consistent with the lack of the NH2-terminal region of PrPc, C1 is more acidic than PrPc and does not bind heparin. An additional fragment longer than C1, designated C2, is present in substantial amounts in CJD brains. Like PrPres, C2 is resistant to proteases and is detergent-insoluble. Our data indicate that C1 is a major product of normal PrPc metabolism, generated by a cleavage that disrupts the neurotoxic and amyloidogenic region of PrP comprising residues 106-126. This region remains intact in C2, suggesting a role for C2 in prion diseases.