Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions
Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions
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DOI：
10.1172/jci200216781
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发表时间：
2002-11-01
影响因子：
15.9
通讯作者：
Horwich, A
中科院分区：
文献类型：
--
作者：
Horwich, A
使用的非标准缩写：内质网（ER）;磷酸甘油酸激酶（PGK）;牛生长激素（bGH）;甲状腺素运载蛋白（TTR）。它们中的许多表现出所谓的双态动力学，即仅在未折叠状态和天然状态之间穿梭，通常在几秒或更短的时间尺度上。这个过程似乎不是随机的，因为所需的搜索时间将是不可能的长;相反，未折叠的蛋白质在到达天然状态的过程中经历了特定的动力学优选步骤，尽管在任何给定的点可能有多种选择（见图1a）。由Alan Fersht和他的同事开创的通过突变分析来检查双态折叠反应的过渡态的能力，允许确定过渡态存在的结构元素，并提供关于天然蛋白质在折叠过程中形成的结构特征的信息（12）。蛋白质似乎遵循多种途径过渡状态。例如，一些蛋白质在组织三级结构之前快速获得二级结构（已经存在于过渡态）;对于其他蛋白质，疏水区域的快速塌陷形成核心可以在二级和三级结构形成之前或同时发生。从大卫贝克和同事最近的工作中一个有趣的观察是，在最终的三维天然状态下，其连续氨基酸序列通过二级或三级结构保持彼此接触的蛋白质比其局部结构由远距离分离的序列形成的蛋白质折叠得更快（例如，在平行β折叠中），这意味着将后者蛋白质中的多肽的远距离片段聚集在一起的熵罚分（13）。
Nonstandard abbreviations used: endoplasmic reticulum (ER); phosphoglycerate kinase (PGK); bovine growth hormone (bGH); transthyretin (TTR). urant, many of them exhibiting what are called twostate kinetics, that is, traversing only between the unfolded and native states, usually on the time scale of a few seconds or less. A wealth of studies of such proteins has begun to define the modes by which proteins fold into their native forms. The process does not appear to be random, as the search time required would be impossibly long; rather, the unfolded protein undergoes specific kinetically preferred steps on the way to the native state, albeit that there may be multiple choices at any given point (see Figure 1a). The ability to examine the transition states for two-state folding reactions by mutation analyses, pioneered by Alan Fersht and his colleagues, allows determination of the elements of structure that are present at the transition state and provides information on which structural features of the native protein have formed during folding up to a given point (12). Proteins appear to follow multiple approaches to the transition state. For example, some proteins rapidly acquire secondary structure (which is present already at the transition state) before organizing tertiary structure; for others, a rapid collapse of hydrophobic regions to form a core can occur before or at the same time as secondary and tertiary structure formation. An interesting observation from the recent work of David Baker and coworkers is that proteins whose contiguous amino acid sequences remain in contact with each other via secondary or tertiary structure in the final three-dimensional native state fold faster than those whose local structures are formed from distantly separated sequences (in a parallel β-sheet, for instance), implying an entropic penalty for bringing together the distant segments of polypeptide in the latter proteins (13).