Mass Spectrometry Reveals a Multifaceted Role of Glycosaminoglycan Chains in Factor Xa Inactivation by Antithrombin

Biochemistry
Burcu Baykal MinskyIgor A Kaltashov

Abstract

Factor Xa (fXa) inhibition by antithrombin (AT) enabled by heparin or heparan sulfate is critical for controlling blood coagulation. AT activation by heparin has been investigated extensively, while interaction of heparin with trapped AT/fXa intermediates has received relatively little attention. We use native electrospray ionization mass spectrometry to study the role of heparin chains of varying length [hexa-, octa-, deca-, and eicosasaccharides (dp6, dp8, dp10, and dp20, respectively)] in AT/fXa complex assembly. Despite being critical promoters of AT/Xa binding, shorter heparin chains are excluded from the final products (trapped intermediates). However, replacement of short heparin segments with dp20 gives rise to a prominent ionic signal of ternary complexes. These species are also observed when the trapped intermediate is initially prepared in the presence of a short oligoheparin (dp6), followed by addition of a longer heparin chain (dp20), indicating that binding of heparin to AT/fXa complexes takes place after the inhibition event. The importance of the heparin chain length for its ability to associate with the trapped intermediate suggests that the binding likely occurs in a bidentate fashion (where two distinct segme...Continue Reading

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Citations

Jun 27, 2020·Angewandte Chemie·Katharina AchaziGerd Multhaup
Sep 18, 2020·Molecular & Cellular Proteomics : MCP·Lauren E PepiI Jonathan Amster
Feb 25, 2020·Journal of Pharmaceutical and Biomedical Analysis·Igor A KaltashovGuanbo Wang
Nov 7, 2019·Analytical Chemistry·David Foreman, Scott A McLuckey

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