Crystal structure of monomeric human β-2-microglobulin reveals clues to its amyloidogenic properties

被引:156
作者
Trinh, CH [1 ]
Smith, DP [1 ]
Kalverda, AP [1 ]
Phillips, SEV [1 ]
Radford, SE [1 ]
机构
[1] Univ Leeds, Astbury Ctr Struct Mol Biol, Sch Biochem & Mol Biol, Leeds LS2 9JT, W Yorkshire, England
基金
英国生物技术与生命科学研究理事会;
关键词
D O I
10.1073/pnas.152337399
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Dissociation of human beta-2-microglobulin (beta(2)M) from the heavy chain of the class I HLA complex is a critical first step in the formation of amyloid fibrils from this protein. As a consequence of renal failure, the concentration of circulating monomeric 62M increases, ultimately leading to deposition of the protein into amyloid fibrils and development of the disorder, dialysis-related amyloidosis. Here we present the crystal structure of a monomeric form of human beta(2)m determined at 1.8-Angstrom resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a beta bulge that separates two short beta strands to form a new six-residue beta strand at one edge of this beta sandwich protein. These structural changes remove key features proposed to have evolved to protect beta sheet proteins from aggregation [Richardson, J. & Richardson, D. (2002) Proc. Nad. Acad Sci. USA 99, 2754-2759] and replaces them with an aggregation-competent surface. in combination with solution studies using H-1 NMR, we show that the crystal structure presented here represents a rare species in solution that could provide important clues about the mechanism of amyloid formation from the normally highly soluble native protein.,
引用
收藏
页码:9771 / 9776
页数:6
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