Department of Urology, James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
J Cell Biochem. 2011 Jul;112(7):1949-52. doi: 10.1002/jcb.23115.
Most proteins encoded by the nuclear genome are synthesized in the cytoplasm and fold into precise 3D structures. During synthesis, the nascent polypeptide begins to fold as it traverses the large subunit of the ribosome and is assisted by molecular chaperones in attaining its precise folded/highly ordered state efficiently and in a biologically relevant timescale. Proteins that are misfolded are culled, re-routed, and marked by mechanisms such as ubiquitinylation for degradation ensuring strict quality control (QC). In addition to the highly ordered "globular" proteins, emerging evidence indicates that a large fraction of the proteome also comprises the so-called "Intrinsically Disordered Proteins" (IDPs). IDPs are proteins that lack rigid 3D structures and instead, exist as dynamic ensembles. The dynamic structures in the IDPs have many similarities with "normal" globular proteins such as the native (ordered), and non-native (molten globule, pre-molten globule, and coil-like) states seen during folding of "normal" globular proteins. However, unlike the case of the nascent globular proteins, IDPs evade being detected as "misfolded" and degraded by the cell's QC system. We refer to this paradox as the order/disorder paradox and postulate that the IDPs capitalize on their intrinsic promiscuity and ability to undergo disorder-to-order transitions upon binding to biological targets (coupled folding and binding) to escape the cell's surveillance machinery. Understanding the mechanism by which the IDPs evade the quality check has wide implications from protein folding to disease biology since the aggregation of misfolded proteins underlies several debilitating illnesses such as many neurodegenerative diseases and cancer.
大多数由核基因组编码的蛋白质在细胞质中合成，并折叠成精确的三维结构。在合成过程中，新生多肽在穿过核糖体大亚基时开始折叠，并在分子伴侣的协助下，有效地以生物学相关的时间尺度达到其精确折叠/高度有序的状态。错误折叠的蛋白质被剔除、重新定向，并通过泛素化等机制标记进行降解，以确保严格的质量控制（QC）。除了高度有序的“球状”蛋白质外，越来越多的证据表明，很大一部分蛋白质组还包括所谓的“内在无序蛋白质”（IDPs）。IDPs 是缺乏刚性 3D 结构的蛋白质，而是以动态集合的形式存在。IDPs 的动态结构与“正常”球状蛋白质有许多相似之处，例如在“正常”球状蛋白质折叠过程中观察到的天然（有序）和非天然（熔融球蛋白、预熔融球蛋白和卷曲状）状态。然而，与新生球状蛋白质的情况不同，IDPs 逃避了细胞 QC 系统对其作为“错误折叠”和降解的检测。我们将这种悖论称为秩序/无序悖论，并假设 IDPs 利用其内在的混杂性和在与生物靶标结合时发生无序到有序转变的能力（偶联折叠和结合）来逃避细胞的监测机制。了解 IDPs 逃避质量检查的机制从蛋白质折叠到疾病生物学都具有广泛的意义，因为错误折叠蛋白质的聚集是许多使人衰弱的疾病的基础，如许多神经退行性疾病和癌症。
