A molecular model for self-assembly of amyloid fibrils: immunoglobulin light chains.
A molecular model for self-assembly of amyloid fibrils: immunoglobulin light chains.
复制标题
淀粉样原纤维自组装的分子模型：免疫球蛋白轻链。
DOI：
10.1021/bi00034a001
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发表时间：
1995
期刊：
影响因子：
2.9
通讯作者：
Schiffer,M
中科院分区：
文献类型：
--
作者：
Stevens,FJ;Myatt,EA;Chang,CH;Westholm,FA;Eulitz,M;Weiss,DT;Murphy,C;Solomon,A;Schiffer,M
淀粉样蛋白原纤维的形成和病理性沉积是许多获得性和遗传性疾病的定义特征，包括原发性或轻链相关淀粉样变性、阿尔茨海默病和成人发病糖尿病。没有药理学方法可以阻断这一过程或实现从组织中去除原纤维，因此，几乎无法预防淀粉样蛋白沉积导致的器官衰竭和最终死亡。由于有关淀粉样蛋白形成的生物物理基础的信息相对缺乏，对这些目前无法治愈的疾病的发病机理、治疗或预防的知识是有限的。不同氨基酸序列的抗体轻链显示出不同的淀粉样蛋白形成倾向，因此，可以提供对淀粉样蛋白原纤维的结构组织以及蛋白质自组装的基本机制的了解。我们比较了180种人单克隆轻链的一级结构，并确定了可变区中区分淀粉样蛋白和非淀粉样蛋白相关蛋白的特定残基和位置。我们提出了一个分子模型，占淀粉样蛋白形成的抗体轻f这项工作是由美国能源部，卫生和环境研究办公室，根据合同W-31-109-ENG-38，由USPHS GrantDK 43757，和USPHS研究资助CA 10056从国家癌症研究所。AS是美国癌症协会临床研究教授。应向谁发送信件。*阿贡国家实验室。§现地址：DuPont Merck Pharmaceutical Co.，杜邦实验站，邮政信箱80228，威尔明顿，DE 19880-0228。11 GSF临床分子生物学研究所1田纳西大学医学中心/医学研究生院。
The formation and pathological deposition of amyloid fibrils are defining features of many acquired and inherited disorders, including primary or light-chain-associated amyloidosis, Alzheimer’s disease, and adult-onset diabetes. No pharmacological methods exist to block this process or to effect the removal of fibrils from tissue, and thus, little can be done to prevent organ failure and ultimate death that result from deposition of amyloid. Knowledge of the pathogenesis, treatment, or prevention of these presently incurable diseases is limited due to the relative paucity of information regarding the biophysical basis of amyloid formation. Antibody light chains of different amino acid sequence show differential amyloid-forming tendencies and, as such, can provide insight into the structural organization of amyloid fibrils as well as into basic mechanisms of protein self-assembly. We have compared primary structures of 180 human monoclonal light chains and have identified particular residues and positions within the variable domain thatdifferentiate amyloid-from nonamyloid-associated proteins. We propose a molecular model that accounts for amyloid formationby antibody light f This work was supported by the US Department of Energy, Office of Health and Environmental Research, under Contract W-31-109-ENG-38, by USPHS GrantDK43757, and by USPHS Research Grant CA10056 from the National Cancer Institute. AS is an American Cancer Society Clinical Research Professor.* To whom correspondence should be addressed.* Argonne National Laboratory. § Present address: DuPont Merck Pharmaceutical Co., DuPont Experimental Station, PO Box 80228, Wilmington, DE 19880-0228. 11 GSF Institute for Clinical Molecular Biology. 1 University of Tennessee Medical Center/Graduate School of Medicine.