期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3380-3385
DOI：10.1073/pnas.1502214112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe biomechanics of amyloid underlies its function in living organisms. We use four-dimensional electron microscopy to systematically dissect the nanoscale origins of amyloid elasticity by measuring the bond stiffnesses of the intermolecular forces stabilizing each of its three characteristic packing interfaces. We find amyloid to have a pronounced mechanical anisotropy with longitudinal, hydrogen bonding 20 times stiffer than transverse, amphiphilic, and electrostatic interactions. Such strongly anisotropic elastic properties are likely to give rise to length-dependent mechanical behavior with short fibrils possessing significantly different material properties than longer fibrils. This is of great importance in understanding fibril-membrane interactions and fragmentation mechanisms, both of which are thought to play a crucial role in the spread of amyloid diseases. The amyloid state of polypeptides is a stable, highly organized structural form consisting of laterally associated {beta}-sheet protofilaments that may be adopted as an alternative to the functional, native state. Identifying the balance of forces stabilizing amyloid is fundamental to understanding the wide accessibility of this state to peptides and proteins with unrelated primary sequences, various chain lengths, and widely differing native structures. Here, we use four-dimensional electron microscopy to demonstrate that the forces acting to stabilize amyloid at the atomic level are highly anisotropic, that an optimized interbackbone hydrogen-bonding network within {beta}-sheets confers 20 times more rigidity on the structure than sequence-specific sidechain interactions between sheets, and that electrostatic attraction of protofilaments is only slightly stronger than these weak amphiphilic interactions. The potential biological relevance of the deposition of such a highly anisotropic biomaterial in vivo is discussed.
关键词：nanomechanics ; proteins ; structural dynamics ; 4D electron diffraction
