Nanobodies as structural probes of protein misfolding and fibril formation.
Nanobodies as structural probes of protein misfolding and fibril formation.
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DOI：
10.1007/978-1-61779-968-6_34
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Dobson, Christopher M
中科院分区：
文献类型：
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作者：
De Genst, Erwin;Dobson, Christopher M
肽和蛋白质以淀粉样纤维的形式沉积是影响大脑或各种其他器官和组织的近50种医学疾病的共同特征。这些疾病，包括阿尔茨海默病、帕金森病、朊病毒病和II型糖尿病，对现代世界的公共卫生和经济产生巨大影响。因此，正在进行广泛的研究，以确定潜在的分子机制和决定因素的病理性转化淀粉样蛋白从其可溶性形式成纤维状结构。使用分子探针和生物物理技术，如X射线晶体学，特别是核磁共振光谱，允许详细分析原纤维形成的机制和相关致病性的基本结构和化学特征。纳米抗体是来自骆驼重链抗体的抗原结合结构域，由于其精致的特异性和高亲和力和稳定性，沿着其易于表达和小尺寸，是探测蛋白质聚集的极好工具;后者特别允许它们与NMR光谱学和X射线晶体学结合使用。在本章中，我们将概述如何使用纳米抗体来获得有关淀粉样蛋白形成机制及其与人类疾病联系的性质和起源的详细信息。
The deposition of peptides and proteins as amyloid fibrils is a common feature of nearly 50 medical -disorders affecting the brain or a variety of other organs and tissues. These disorders, which include Alzheimer's disease, Parkinson's disease, the prion diseases, and type II diabetes, have an enormous impact on the public health and economy of the modern world. Extensive research is therefore taking place to determine the underlying molecular mechanisms and determinants of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. The use of molecular probes and biophysical techniques, such as X-ray crystallography and particularly NMR spectroscopy, are allowing detailed analysis of the mechanism of fibril formation and of the underlying structural and chemical features of the associated pathogenicity. Nanobodies, the antigen-binding domains derived from camelid heavy-chain antibodies, are excellent tools to probe protein aggregation as a result of their exquisite specificity and high affinity and stability, along with their ease of expression and small size; the latter in particular allows them to be used very efficiently in combination with NMR spectroscopy and X-ray crystallography. In this chapter we present an overview of how nanobodies are being used to obtain detailed information on the mechanisms of amyloid formation and on the nature and origin of their links with human diseases.