Crystal structure of monomeric human β-2-microglobulin reveals clues to its amyloidogenic properties
10.1073/pnas.152337399
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
Abstract

Dissociation of human β-2-microglobulin (β 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 β 2 m 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 β 2 m determined at 1.8-Å resolution that reveals remarkable structural changes relative to the HLA-bound protein. These involve the restructuring of a β bulge that separates two short β strands to form a new six-residue β strand at one edge of this β sandwich protein. These structural changes remove key features proposed to have evolved to protect β sheet proteins from aggregation [Richardson, J. & Richardson, D. (2002) Proc. Natl. Acad. Sci. USA 99, 2754–2759] and replaces them with an aggregation-competent surface. In combination with solution studies using 1 H 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.

Bibliography

Trinh, C. H., Smith, D. P., Kalverda, A. P., Phillips, S. E. V., & Radford, S. E. (2002). Crystal structure of monomeric human β-2-microglobulin reveals clues to its amyloidogenic properties. Proceedings of the National Academy of Sciences, 99(15), 9771–9776.

Authors 5
  1. Chi H. Trinh (first)
  2. David P. Smith (additional)
  3. Arnout P. Kalverda (additional)
  4. Simon E. V. Phillips (additional)
  5. Sheena E. Radford (additional)
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Dates
Type When
Created 23 years, 1 month ago (July 28, 2002, 6:26 p.m.)
Deposited 3 years, 2 months ago (June 7, 2022, 1:46 a.m.)
Indexed 1 week, 3 days ago (Aug. 24, 2025, 6:54 p.m.)
Issued 23 years, 1 month ago (July 15, 2002)
Published 23 years, 1 month ago (July 15, 2002)
Published Online 23 years, 1 month ago (July 15, 2002)
Published Print 23 years, 1 month ago (July 23, 2002)
Funders 0

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@article{Trinh_2002, title={Crystal structure of monomeric human β-2-microglobulin reveals clues to its amyloidogenic properties}, volume={99}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.152337399}, DOI={10.1073/pnas.152337399}, number={15}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Trinh, Chi H. and Smith, David P. and Kalverda, Arnout P. and Phillips, Simon E. V. and Radford, Sheena E.}, year={2002}, month=jul, pages={9771–9776} }