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β2-Microglobulin and Dialysis-Related Amyloidosis

  • Chapter
Protein Misfolding, Aggregation, and Conformational Diseases

Part of the book series: Protein Reviews ((PRON,volume 6))

Abstract

β2-Microglobulin (β2m) is the noncovalently bound component of the class I major histocompatibility complex (MHC) and is one of more than 20 proteins that are known to cause human amyloid disease. β2m is degraded and excreted by the kidney as part of its normal catabolic cycle. In patients suffering renal failure, therefore, the principal mechanism of β2m degradation is abrogated, with the consequence that the concentration of β2m in the serum increases by up to 60-fold, which leads to the association of freely circulating β2m into insoluble amyloid fibrils, which typically accumulate in the musculoskeletal system, causing dialysis-related amyloidosis (DRA). The unique environment of the synovial joint may also be an important feature in stimulating β2m deposition in a fibrillar form, although the factors that play the key role in the development and deposition of β2m amyloid in this compartment remain unclear. In this chapter, we outline the events involved in the development of DRA. We discuss biophysical and biochemical studies of β2m fibrillogenesis in vitro and summarize the insights that these studies have provided into the structural molecular mechanism of its self-association into amyloid fibrils. We then discuss the role of different biological factors in influencing amyloid formation in vitro and in vivo, highlighting key questions about the mechanism of aggregation of β2m into amyloid fibrils that have arisen from these studies. Finally we discuss routes forward in the search for potential new therapies for DRA patients.

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  1. Astbury Centre for Structural Molecular Biology, School of Biochemistry and Microbiology, University of Leeds, Leeds, LS2 9JT, UK

    Isobel J. Morten, Eric W. Hewitt & Sheena E. Radford

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  2. Eric W. Hewitt
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  1. Department of Biochemistry and Molecular Biology, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202

    Vladimir N. Uversky

  2. Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia

    Vladimir N. Uversky

  3. Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064, USA

    Anthony L. Fink

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Morten, I.J., Hewitt, E.W., Radford, S.E. (2007). β2-Microglobulin and Dialysis-Related Amyloidosis. In: Uversky, V.N., Fink, A.L. (eds) Protein Misfolding, Aggregation, and Conformational Diseases. Protein Reviews, vol 6. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-36534-3_11

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