Kelly J W
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Curr Opin Struct Biol. 1998 Feb;8(1):101-6. doi: 10.1016/s0959-440x(98)80016-x.
The conformational change hypothesis postulates that tertiary structural changes under partially denaturing conditions convert one of 17 normally soluble and functional human proteins into an alternative conformation that subsequently undergoes self-assembly into an amyloid fibril, the putative causative agent in amyloid disease. This hypothesis is consistent with Anfinsen's view that the tertiary structure of a protein is determined both by its sequence and the aqueous environment; the latter does not always favor the normally folded state. Unlike sickle cell hemoglobin assembly, where owing to a surface mutation, hemoglobin polymerizes in its normally folded conformation, amyloid proteins self-assemble as a result of the formation of an alternative tertiary structure-a conformational intermediate formed under partially denaturing conditions. The pathway by which an amyloidogenic protein assembles into amyloid fibrils appears to involve quaternary structural intermediates that assemble into increasingly complex quaternary structures, including amyloid protofilaments, which ultimately assemble into amyloid fibrils. Several recent studies have discussed the multi-step assembly pathway(s) characterizing amyloid fibril formation.
构象变化假说认为，在部分变性条件下的三级结构变化会将17种正常可溶且有功能的人类蛋白质之一转变为另一种构象，随后这种构象会自我组装成淀粉样纤维，而淀粉样纤维被认为是淀粉样疾病的致病因子。这一假说与安芬森的观点一致，即蛋白质的三级结构由其序列和水环境共同决定；后者并不总是有利于正常折叠状态。与镰状细胞血红蛋白组装不同，由于表面突变，血红蛋白在其正常折叠构象中发生聚合，淀粉样蛋白是由于形成了另一种三级结构（在部分变性条件下形成的构象中间体）而自我组装的。淀粉样蛋白组装成淀粉样纤维的途径似乎涉及四级结构中间体，这些中间体组装成越来越复杂的四级结构，包括淀粉样原纤维，最终组装成淀粉样纤维。最近的几项研究讨论了表征淀粉样纤维形成的多步组装途径。
