Gorbenko Galyna P, Kinnunen Paavo K J
Department of Biological and Medical Physics, VN Karazin Kharkiv National University, Ukraine.
Chem Phys Lipids. 2006 Jun;141(1-2):72-82. doi: 10.1016/j.chemphyslip.2006.02.006. Epub 2006 Mar 10.
Structural transition of polypeptide chains into the beta-sheet state followed by amyloid fibril formation is the key characteristic of a number of the so-called conformational diseases. The multistep process of protein fibrillization can be modulated by a variety of factors, in particular by lipid-protein interactions. A wealth of experimental evidence provides support to the notion that amyloid fibril assembly and the toxicity of pre-fibrillar aggregates are closely related and are both intimately membrane associated phenomena. The present review summarizes the principal factors responsible for the enhancement of fibril formation in a membrane environment, viz. (i) structural transformation of polypeptide chain into a partially folded conformation, (ii) increase of the local concentration of a protein upon its membrane binding, (iii) aggregation-favoring orientation of the bound protein, and (iv) variation in the depth of bilayer penetration affecting the nucleation propensity of the membrane associated protein. The molecular mechanisms of membrane-mediated protein fibrillization are discussed. Importantly, the toxicity of lipid-induced pre-fibrillar aggregates is likely to have presented a very strong negative selection pressure in the evolution of amino acid sequences.
多肽链向β-折叠状态的结构转变，随后形成淀粉样纤维，是许多所谓构象疾病的关键特征。蛋白质纤维化的多步骤过程可受多种因素调节，尤其是脂质-蛋白质相互作用。大量实验证据支持以下观点：淀粉样纤维组装和纤维前聚集体的毒性密切相关，且都是与膜紧密相关的现象。本综述总结了在膜环境中增强纤维形成的主要因素，即：(i)多肽链向部分折叠构象的结构转变；(ii)蛋白质与膜结合后局部浓度的增加；(iii)结合蛋白有利于聚集的取向；(iv)双层穿透深度的变化影响膜相关蛋白的成核倾向。文中讨论了膜介导的蛋白质纤维化的分子机制。重要的是，脂质诱导的纤维前聚集体的毒性可能在氨基酸序列的进化中呈现出非常强大的负选择压力。
