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首页> 外文学位 >Biophysical approaches for the determination of the effects of multiple sclerosis-like mutations on myelin basic protein.
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Biophysical approaches for the determination of the effects of multiple sclerosis-like mutations on myelin basic protein.

机译：用于确定多发性硬化样突变对髓鞘碱性蛋白的影响的生物物理方法。

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摘要

Multiple Sclerosis (MS) is a chronic demyelinating disease that affects the central nervous system and is thought to be an autoimmune disorder triggered by both genetic and environmental factors. Myelin basic protein (MBP) is a candidate autoantigen in MS and maintains the compactness of the myelin sheath. MBP undergoes an assortment of post-translational modifications, which leads to a variety of charge isomers. Deimination of arginine residues (charge +1) to citrulline (charge 0) is one of the principal modifications that gives rise to the multivalency of MBP. Charge isoforms are termed C1 to C8, with C8 being the most heavily deiminated and least charged. In the last decade a number of studies have found an association with the more heavily deiminated C8 with victims of MS.; A recombinant murine MBP was used to represent the least modified form of MBP/C1, and was called quasi-C1 (qC1). Using site-directed mutagenesis, Gln substitutions were used to engineer a mimic of the C8 isoform (subsequently called qC8). The qC8 form was found to be less effective at compacting vesicles and to have slightly less structure when bound to micellar or negatively charged lipids. Fluorescence microscopy showed that qC1 and qC8 could bind to G-actin, but only qC1 could organize F-actin into branched bundles.; Long-range molecular dynamics was done on three theoretical models of MBP, with one representing qC1, and the other two representing the citrullinated form found naturally and the quasi-deiminated form (qC8). The molecular dynamics showed that the less charged forms were less globular, and that all forms of the protein showed spontaneous generation of alpha-helices.; Site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) of the two forms of MBP when bound to vesicles emulative of the myelin sheath revealed that the C-terminus of qC8 was significantly more exposed to the aqueous phase than qC1, suggesting increased availability for immune or ligand recognition. Another site of significant importance in the MS field is an immunodominant region between Pro83 to Pro92. SDSL of every residue between Pro83 and Pro92 showed that this important site is an amphipathic alpha-helix when bound to the membrane.
机译：多发性硬化症（MS）是一种慢性脱髓鞘疾病，会影响中枢神经系统，被认为是由遗传和环境因素共同引发的自身免疫性疾病。髓磷脂碱性蛋白（MBP）是MS中的候选自身抗原，可保持髓鞘的致密性。 MBP经历了各种翻译后修饰，这导致了各种电荷异构体。将精氨酸残基（电荷+1）确定为瓜氨酸（电荷0）是引起MBP多价的主要修饰之一。电荷同工型称为C1至C8，C8的去杂基最重，电荷最少。在过去的十年中，许多研究发现，它与MS受害者中C8的含量更高有关。重组鼠类MBP用于代表MBP / C1修饰最少的形式，称为准C1（qC1）。使用定点诱变，Gln取代被用于工程化C8同种型（随后称为qC8）的模拟物。发现qC8形式在压紧囊泡时效果不佳，与胶束或带负电荷的脂质结合时结构稍弱。荧光显微镜显示qC1和qC8可以与G-肌动蛋白结合，但是只有qC1可以将F-肌动蛋白组织成支链束。远程分子动力学在MBP的三个理论模型上完成，一个代表qC1，另外两个代表天然发现的瓜氨酸化形式和准决定的形式（qC8）。分子动力学表明，带电荷较少的形式的球形较小，并且所有形式的蛋白质均显示出自发产生的α-螺旋。两种形式的MBP与髓鞘的小泡结合时的定点自旋标记（SDSL）和顺磁电子（EPR）显示，qC8的C端比qC1显着更多地暴露于水相提高了免疫或配体识别的可用性。在MS领域中另一个重要的位点是Pro83和Pro92之间的一个免疫优势区域。 Pro83和Pro92之间的每个残基的SDSL表明，该重要位点与膜结合时是两亲性α-螺旋。

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  • 作者

    Bates, Ian Randolph.;

  • 作者单位

    University of Guelph (Canada).;

  • 授予单位 University of Guelph (Canada).;
  • 学科 Biophysics General.; Biology Neuroscience.; Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 192 p.
  • 总页数 192
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物物理学;神经科学;生物化学;
  • 关键词

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