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The Role of His-18 in Amyloid Formation by Human Islet Amyloid Polypeptide

机译：他-18在人胰岛淀粉样蛋白多肽的淀粉样蛋白形成中的作用

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摘要

The 37-residue islet amyloid polypeptide(IAPP)is the major protein component of the amyloid deposits found in type-II diabetes.IAPP is stored in a relatively low pH environment in the pancreatic secretory granules prior to its release to the extracellular environment.Human IAPP contains a single histidine at position 18.Aggregation of IAPP is considerably faster at a lower pH(4.0(+-)0.3)than at high pH(8.8(+-)0.3),as judged by turbidity and thioflavine-T fluorescence studies.The rate of aggregation at low pH increases drastically in the presence of salt.CD experiments show that the conversion of largely unstructured monomers to beta-sheet-rich structures is faster at high pH.TEM studies show that fibrils are formed at both pH values but are more prevalent at pH 8.8((+-)0.3).Both the free N terminus of IAPP and His-18 will titrate over the pH range studied.An N-terminal acetylated fragment consisting of residues 8-37 of human IAPP was also studied to isolate contributions from the protonation of His-18.Previous studies have shown that this fragment forms protofibrils that are very similar to those formed by intact IAPP.The effects of varying the protonation state of His-18 in the 8-37 analogue indicate that the rate of aggregation and fibril formation is noticeably faster when His-18 is deprotonated,similar to the wild type.However,the pH-dependent effects are larger for full-length IAPP than for the disulfide-truncated,acetylated analogue.TEM studies indicate differences in the morphology of the deposits formed at high and low pH.These results are discussed in light of recent structural models of IAPP fibrils.
机译：37-残基胰岛淀粉样蛋白多肽（IAPP）是II型糖尿病型淀粉样蛋白沉积物的主要蛋白质组分。在其释放到细胞外环境之前，将PP储存在胰腺分泌物颗粒中的相对低的pH环境中。一起IAPP含有18位的单个组织。IAPP的烧结在低pH（4.0（+ - ）0.3）下比高pH（8.8（+ - ）0.3）更快（8.8（+ - ）0.3），如浊度和硫喷仑-T荧光研究判断。在盐的存在下，低pH的聚集速度急剧增加。实验表明，大量非结构化单体对富含β-片状的结构的转化率在高pH.中的研究表明，原纤维在两个pH值下形成了原纤维但在pH 8.8（（+ - ）0.3）中更普遍还研究了分离ProTO的贡献他-18的国家。另外的研究表明，该片段形成原生料，其与完整的IAPP形成的那些非常相似。在8-37个类似物中，改变他-18的质子化状态的效果表明聚集率和当野生型类似于野生型时，原纤维形成是明显的。然而，对于全长IAPP，pH依赖性效果比二硫化物截短的乙酰化的类似物更大。目录研究​​表明了形态学的差异根据IAPP原纤维最近的结构模型讨论了高低于pH值的沉积物。

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  • 来源
    《Biochemistry》 |2005年第49期|共8页
  • 作者

    Andisheh Abedini; Daniel P.Raleigh;

  • 作者单位

    Department of Chemistry State University of New York at Stony Brook Stony Brook New York 11794-3400 and Graduate Program in Biochemistry and Structural Biology Graduate Program in Biophysics State University of New York at Stony Brook Stony Brook New;

    Department of Chemistry State University of New York at Stony Brook Stony Brook New York 11794-3400 and Graduate Program in Biochemistry and Structural Biology Graduate Program in Biophysics State University of New York at Stony Brook Stony Brook New;

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  • 正文语种 eng
  • 中图分类 生物化学;
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