Cross-Linking Mass Spectrometry Uncovers Interactions Between High-Density Lipoproteins and the SARS-CoV-2 Spike Glycoprotein

Sean A Burnap, Ana Maria Ortega-Prieto, Jose M Jimenez-Guardeño, Hashim Ali, Kaloyan Takov, Matthew Fish, Manu Shankar-Hari, Mauro Giacca, Michael H Malim, Manuel Mayr

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

High-density lipoprotein (HDL) levels are reduced in patients with coronavirus disease 2019 (COVID-19), and the extent of this reduction is associated with poor clinical outcomes. While lipoproteins are known to play a key role during the life cycle of the hepatitis C virus, their influence on coronavirus (CoV) infections is poorly understood. In this study, we utilize cross-linking mass spectrometry (XL-MS) to determine circulating protein interactors of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoprotein. XL-MS of plasma isolated from patients with COVID-19 uncovered HDL protein interaction networks, dominated by acute-phase serum amyloid proteins, whereby serum amyloid A2 was shown to bind to apolipoprotein (Apo) D. XL-MS on isolated HDL confirmed ApoD to interact with SARS-CoV-2 spike but not SARS-CoV-1 spike. Other direct interactions of SARS-CoV-2 spike upon HDL included ApoA1 and ApoC3. The interaction between ApoD and spike was further validated in cells using immunoprecipitation-MS, which uncovered a novel interaction between both ApoD and spike with membrane-associated progesterone receptor component 1. Mechanistically, XL-MS coupled with data-driven structural modeling determined that ApoD may interact within the receptor-binding domain of the spike. However, ApoD overexpression in multiple cell-based assays had no effect upon viral replication or infectivity. Thus, SARS-CoV-2 spike can bind to apolipoproteins on HDL, but these interactions do not appear to alter infectivity.

Original languageEnglish
Article number100600
Pages (from-to)100600
JournalMolecular & Cellular Proteomics (MCP)
Issue number8
Early online date19 Jun 2023
Publication statusPublished - 20 Jul 2023

Keywords / Materials (for Non-textual outputs)

  • XL-MS
  • HDL
  • SARS-CoV-2
  • ApoD
  • spike


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