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β2-microglobulin forms three-dimensional domain-swapped amyloid fibrils with disulfide linkages

Nature Structural & Molecular Biology volume 18, pages 49–55 (2011)Cite this article

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Abstract

β2-microglobulin (β2m) is the light chain of the type I major histocompatibility complex. It deposits as amyloid fibrils within joints during long-term hemodialysis treatment. Despite the devastating effects of dialysis-related amyloidosis, full understanding of how fibrils form from soluble β2m remains elusive. Here we show that β2m can oligomerize and fibrillize via three-dimensional domain swapping. Isolating a covalently bound, domain-swapped dimer from β2m oligomers on the pathway to fibrils, we were able to determine its crystal structure. The hinge loop that connects the swapped domain to the core domain includes the fibrillizing segment LSFSKD, whose atomic structure we also determined. The LSFSKD structure reveals a class 5 steric zipper, akin to other amyloid spines. The structures of the dimer and the zipper spine fit well into an atomic model for this fibrillar form of β2m, which assembles slowly under physiological conditions.

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Figure 1: Characterization of β2m oligomers.
Figure 2: Refolding and purification of β2m dimer.
Figure 3: Structure of the domain-swapped β2m dimer.
Figure 4: Systematic screening for amyloidogenic segments in the hinge loop (residues 52–65).
Figure 5: Crystal structure of segment LSFSKD and schematics for β2m fibrillation.

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Acknowledgements

We thank the Northeastern Collaborative Access Team facility at the Advanced Photon Source at Argonne National Laboratory for beam time and collection assistance, and S. Radford, M. Bennett and Z. Guo for discussion. This work was supported by the US National Institutes of Health, the US Department of Energy Biological and Environmental Research program and the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. University of California Los Angeles–United States Department of Energy Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, California, USA

    Cong Liu, Michael R Sawaya & David Eisenberg

  2. Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, California, USA

    Cong Liu, Michael R Sawaya & David Eisenberg

  3. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA

    Cong Liu, Michael R Sawaya & David Eisenberg

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  1. Cong Liu
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Contributions

C.L. designed the research, with advice from D.E., and carried out all the experiments; M.R.S. calculated and built the fibril models; C.L. wrote the paper; all authors discussed the results and revised the manuscript; D.E. supervised the work.

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Correspondence to David Eisenberg.

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The authors declare no competing financial interests.

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Liu, C., Sawaya, M. & Eisenberg, D. β2-microglobulin forms three-dimensional domain-swapped amyloid fibrils with disulfide linkages. Nat Struct Mol Biol 18, 49–55 (2011). https://doi.org/10.1038/nsmb.1948

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