Investigation of D76N β2-Microglobulin Using Protein Footprinting and Structural Mass Spectrometry.

串联质谱法 电喷雾电离 色谱法 离子迁移光谱法 离解(化学)
作者
Owen Cornwell,James R. Ault,Nicholas J. Bond,Sheena E. Radford,Alison E. Ashcroft
出处
期刊:Journal of the American Society for Mass Spectrometry [American Chemical Society]
卷期号:32 (7): 1583-1592 被引量:1
标识
DOI:10.1021/jasms.0c00438
摘要

NMR studies and X-ray crystallography have shown that the structures of the 99-residue amyloidogenic protein β2-microglobulin (β2m) and its more aggregation-prone variant, D76N, are indistinguishable, and hence, the reason for the striking difference in their aggregation propensities remains elusive. Here, we have employed two protein footprinting methods, hydrogen-deuterium exchange (HDX) and fast photochemical oxidation of proteins (FPOP), in conjunction with ion mobility-mass spectrometry, to probe the differences in conformational dynamics of the two proteins. Using HDX-MS, a clear difference in HDX protection is observed between these two proteins in the E-F loop (residues 70-77) which contains the D76N substitution, with a significantly higher deuterium uptake being observed in the variant protein. Conversely, following FPOP-MS only minimal differences in the level of oxidation between the two proteins are observed in the E-F loop region, suggesting only modest side-chain movements in that area. Together the HDX-MS and FPOP-MS data suggest that a tangible perturbation to the hydrogen-bonding network in the E-F loop has taken place in the D76N variant and furthermore illustrate the benefit of using multiple complementary footprinting methods to address subtle, but possibly biologically important, differences between highly similar proteins.
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