Krebs Mark R H, Domike Kristin R, Donald Athene M
Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK.
Biochem Soc Trans. 2009 Aug;37(Pt 4):682-6. doi: 10.1042/BST0370682.
The aggregation of misfolded proteins into amyloid fibrils, and the importance of this step for various diseases, is well known. However, it is becoming apparent that the fibril is not the only structure that aggregating proteins of widely different types may adopt. Around the isoelectric point, when the net charge is essentially zero, rather monodisperse and quasi-amorphous nanoscale particles form. These particles are found to contain limited runs of beta-sheet structure, but their overall organization is random. These nanoparticles have the potential to be useful for such applications as the slow release of drugs. The amyloid fibrils form away from the isoelectric point, but over certain ranges of, e.g., pH, the fibrils themselves do not exist freely, but form suprafibrillar aggregates termed spherulites. These consist of fibrils radiating from a central nucleus, and form by new species attaching to the ends of growing fibrils, rather than by the aggregation of pre-existing fibrils. Under the polarizing light microscope, they exhibit a Maltese cross shape due to their symmetry. The rate of aggregation is determined by factors involving (at least) protein size, concentration, presence of salt and charge. The occurrence of spherulites, which have been found in vivo as well as in vitro, appears to be generic, although the factors which determine the equilibrium between free fibril and spherulite are not as yet clear.
错误折叠的蛋白质聚集成淀粉样纤维，以及这一步骤对各种疾病的重要性，是众所周知的。然而，越来越明显的是，纤维并不是广泛不同类型的聚集蛋白可能采用的唯一结构。在等电点附近，当净电荷基本为零时，会形成相当单分散且准无定形的纳米级颗粒。发现这些颗粒包含有限的β-折叠结构片段，但其整体结构是随机的。这些纳米颗粒有可能用于药物缓释等应用。淀粉样纤维在远离等电点的条件下形成，但在例如特定的pH范围内，纤维本身并非自由存在，而是形成称为球晶的超纤维聚集体。这些球晶由从中央核辐射出的纤维组成，是通过新的物种附着在生长纤维的末端形成的，而不是由预先存在的纤维聚集形成。在偏光显微镜下，由于其对称性，它们呈现出马尔他十字形状。聚集速率由（至少）涉及蛋白质大小、浓度、盐的存在和电荷的因素决定。球晶在体内和体外均已被发现，其出现似乎具有普遍性，尽管决定自由纤维和球晶之间平衡的因素尚不清楚。
