Comparison of the aggregation of homologous β2-microglobulin variants reveals protein solubility as a key determinant of amyloid formation

Journal of Molecular Biology
Clare L PashleySheena E Radford

Abstract

The mouse and human β2-microglobulin protein orthologs are 70% identical in sequence and share 88% sequence similarity. These proteins are predicted by various algorithms to have similar aggregation and amyloid propensities. However, whilst human β2m (hβ2m) forms amyloid-like fibrils in denaturing conditions (e.g. pH2.5) in the absence of NaCl, mouse β2m (mβ2m) requires the addition of 0.3M NaCl to cause fibrillation. Here, the factors which give rise to this difference in amyloid propensity are investigated. We utilise structural and mutational analyses, fibril growth kinetics and solubility measurements under a range of pH and salt conditions, to determine why these two proteins have different amyloid propensities. The results show that, although other factors influence the fibril growth kinetics, a striking difference in the solubility of the proteins is a key determinant of the different amyloidogenicity of hβ2m and mβ2m. The relationship between protein solubility and lag time of amyloid formation is not captured by current aggregation or amyloid prediction algorithms, indicating a need to better understand the role of solubility on the lag time of amyloid formation. The results demonstrate the key contribution of protein ...Continue Reading

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Citations

Apr 28, 2016·Journal of the American Chemical Society·Theodoros K KaramanosSheena E Radford
Feb 6, 2017·Drug Delivery·Yaron DekelJacob Pitcovski
Jun 22, 2021·Current Opinion in Structural Biology·Sara Linse

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Methods Mentioned

BETA
NMR
gel filtration

Software Mentioned

NMRView
NMRPipe
SEDFIT
Zyggregator
TANGO
CamSol

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