日前,美国《国家科学院院刊》(PNAS)在线发表了国家纳米科学中心科研人员的淀粉样蛋白结构解析的新进展。研究人员利用扫描隧道显微技术(STM)对2型糖尿病相关的淀粉样蛋白——胰淀素的组装和聚集结构进行研究,确定了淀粉样蛋白组装和聚集的核心片段及折叠位点,并讨论了突变引起的聚集趋势的变化与核心片段之间的关联。对理解淀粉样蛋白的核心片段与其致病性之间的关系有重要意义。
理解淀粉样蛋白的折叠结构和聚集行为是检测和治疗淀粉样病变的关键所在。但是由于淀粉样蛋白不易结晶,而且溶解性差,使得结构解析非常困难。近几年来,国家纳米科学中心科研人员发展了一种利用小分子调节剂有效调控淀粉样蛋白聚集的新方法,探索在分子水平上开展对淀粉样多肽的结构的解析研究,进一步发现通过调控其组装结构和聚集过程可以有效地降低淀粉样多肽的细胞毒性。参与此研究的骨干成员毛晓波、王晨轩等还利用扫描隧道显微方法研究了淀粉样多肽与标记分子的结合模式。这些工作提出了一种新颖的淀粉样多肽结构解析方法,而且从分子水平上揭示了多肽与分子调节剂相互作用的机理,为与淀粉样蛋白聚集有关的疾病预防、药物设计和治疗提供了新思路。(生物谷Bioon.com)
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doi:10.1073/pnas.1102971108
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PMID:
Beta structure motifs of islet amyloid polypeptides identified through surface-mediated assemblies
Mao, Xiao-Bo; Wang, Chen-Xuan; Wu, Xing-Kui; Ma, Xiao-Jing; Liu, Lei; Zhang, Lan; Niu, Lin; Guo, Yuan-Yuan; Li, Deng-Hua; Yang, Yan-Lian; Wang, Chen
We report here the identification of the key sites for the beta structure motifs of the islet amyloid polypeptide (IAPP) analogs by using scanning tunneling microscopy (STM). Duplex folding structures in human IAPP8–37 (hIAPP8–37) assembly were observed featuring a hairpin structure. The multiplicity in rIAPP assembly structures indicates the polydispersity of the rat IAPP8–37 (rIAPP8–37) beta-like motifs. The bimodal length distribution of beta structure motifs for rIAPP8–37 R18H indicates the multiple beta segments linked by turns. The IAPP8–37 analogs share common structure motifs of IAPP8–17 and IAPP26–37 with the most probable key sites at positions around Ser19/Ser20 and Gly24. These observations reveal the similar amyloid formation tendency in the C and N terminus segments because of the sequence similarity, while the differences in specific amino acids at each key site manifest the effect of sequence variations. The results could be beneficial for studying structural polymorphism of amyloidal peptides with multiple beta structure motifs.