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

Molecular BioSystems
Aneika C LeneyAlison E Ashcroft

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...Continue Reading

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Citations

Jul 21, 2015·FEBS Letters·Leonid Breydo, Vladimir N Uversky
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Sep 11, 2021·Chemical Reviews·Hannah M BrittKonstantinos Thalassinos

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Methods Mentioned

BETA
X-ray
NMR
electron microscopy
transmission electron microscopy

Software Mentioned

MassLynx
Driftscope
SEDFIT

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