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Issue 3, 2014
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Insights into the role of the beta-2 microglobulin D-strand in amyloid propensity revealed by mass spectrometry

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Abstract

In vivo beta-2 microglobulin (β2m) forms amyloid fibrils that are associated with the disease dialysis-related amyloidosis. Here, electrospray ionisation-ion mobility spectrometry-mass spectrometry has been used to compare the oligomers formed from wild-type β2m with those formed from a variant of the protein containing a single point mutation in the D strand, H51A, during in vitro fibril assembly. Using the amyloid-binding fluorescent dye, Thioflavin T, to monitor fibrillation kinetics, H51A was shown to exhibit a two-fold increase in the lag-time of fibril formation. Despite this, comparison of the oligomeric species observed during the lag-time of self-aggregation indicated that H51A had a higher population of oligomers, and formed oligomers of higher order, than wild-type β2m. The cross-sectional areas of the oligomers arising from H51A and wild-type protein were indistinguishable, although the H51A oligomers were shown to have a significantly higher kinetic stability on account of their reluctance to undergo sub-unit exchange when mixed with 15N-labelled protein. Together the data reveal a significant effect of His51, and thus that of the D-strand sequence, on amyloid formation. The results also highlight the power of mass spectrometry in probing complex biochemical mechanisms in real-time.

Graphical abstract: Insights into the role of the beta-2 microglobulin D-strand in amyloid propensity revealed by mass spectrometry

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Publication details

The article was received on 20 Sep 2013, accepted on 06 Dec 2013 and first published on 09 Dec 2013


Article type: Paper
DOI: 10.1039/C3MB70420C
Citation: Mol. BioSyst., 2014,10, 412-420
  • Open access: Creative Commons BY license
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    Insights into the role of the beta-2 microglobulin D-strand in amyloid propensity revealed by mass spectrometry

    A. C. Leney, C. L. Pashley, C. A. Scarff, S. E. Radford and A. E. Ashcroft, Mol. BioSyst., 2014, 10, 412
    DOI: 10.1039/C3MB70420C

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