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Ion Mobility Mass Spectrometry Analysis of Oxygen Affinity-Associated Structural Changes in Hemoglobin

  • Chae Eun Heo
    Chae Eun Heo
    Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
    Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
    More by Chae Eun Heo
  • Minji Kim
    Minji Kim
    Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
    Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
    More by Minji Kim
  • Myung Kook Son
    Myung Kook Son
    Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
    Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
  • Da Gyeong Hyun
    Da Gyeong Hyun
    Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
    Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
  • Sung Woo Heo*
    Sung Woo Heo
    Inorganic Metrology Group, Division of Chemical and Biological Metrology, Korea Research Institute of Standards and Science (KRISS), Daejeon 34113, Republic of Korea
    *Sung Woo Heo ([email protected]).
    More by Sung Woo Heo
  • , and 
  • Hugh I. Kim*
    Hugh I. Kim
    Department of Chemistry, Korea University, Seoul 02841, Republic of Korea
    Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea
    *Hugh I. Kim ([email protected]).
    More by Hugh I. Kim
Cite this: J. Am. Soc. Mass Spectrom. 2021, 32, 10, 2528–2535
Publication Date (Web):August 31, 2021
https://doi.org/10.1021/jasms.1c00161
Copyright © 2021 American Society for Mass Spectrometry. Published by American Chemical Society. All rights reserved.

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    Abstract

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    Hemoglobin (Hb) is a major oxygen-transporting protein with allosteric properties reflected in the structural changes that accompany binding of O2. Glycated hemoglobin (GHb), which is a minor component of human red cell hemolysate, is generated by a nonenzymatic reaction between glucose and hemoglobin. Due to the long lifetime of human erythrocytes (∼120 days), GHb is widely used as a reliable biomarker for monitoring long-term glucose control in diabetic patients. Although the structure of GHb differs from that of Hb, structural changes relating to the oxygen affinity of these proteins remain incompletely understood. In this study, the oxygen-binding kinetics of Hb and GHb are evaluated, and their structural dynamics are investigated using solution small-angle X-ray scattering (SAXS), electrospray ionization mass spectrometry equipped with ion mobility spectrometry (ESI-IM-MS), and molecular dynamic (MD) simulations to understand the impact of structural alteration on their oxygen-binding properties. Our results show that the oxygen-binding kinetics of GHb are diminished relative to those of Hb. ESI-IM-MS reveals structural differences between Hb and GHb, which indicate the preference of GHb for a more compact structure in the gas phase relative to Hb. MD simulations also reveal an enhancement of intramolecular interactions upon glycation of Hb. Therefore, the more rigid structure of GHb makes the conformational changes that facilitate oxygen capture more difficult creating a delay in the oxygen-binding process. Our multiple biophysical approaches provide a better understanding of the allosteric properties of hemoglobin that are reflected in the structural alterations accompanying oxygen binding.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jasms.1c00161.

    • Experimental conditions; methods for data analysis; Figure S1, UV–vis spectra of Hb and GHb treated with O2 gas; Figure S2, Agilent 6560 ESI-MS data of Hb and GHb; Supporting Note I, analysis of Agilent 6560 ESI-MS; Figure S3, calibration curves of the ESI-MS; Figure S4, CCS distributions of tetrameric Hb and GHb in the +17, + 18, and +19 charge states; Figure S5, arrival time distributions of tetrameric Hb and GHb with the +17 and +18 charge states obtained using the Agilent 6560 DTIM-MS; Supporting Note II, analysis of Figure S5; Figure S6, ESI-IMMS spectra of Hb and GHb obtained using the Agilent 6560 DTIM-MS, from m/z range 3250–4000; Figure S7, ESI-IMMS spectra of tetrameric Hb and GHb with the +17 and +18 charge states obtained using Agilent 6560 DTIM-MS, at various conditions; Figure S8, experimental and theoretical SAXS scattering profiles of Hb and GHb; Figure S9, P(r) distributions and Dmax values of Hb and GHb; Figure S10, calibration curve for CCS values obtained using Synapt G2-Si; Table S1, complete sequence of digested GHb peptides with trp, chp, and GluC enzymes (PDF)

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    Cited By

    This article is cited by 1 publications.

    1. Daniel G. Delafield, Gaoyuan Lu, Cameron J. Kaminsky, Lingjun Li. High-end ion mobility mass spectrometry: A current review of analytical capacity in omics applications and structural investigations. TrAC Trends in Analytical Chemistry 2022, 157 , 116761. https://doi.org/10.1016/j.trac.2022.116761