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J Biol Chem. 2019 May 31;294(22):8773-8778. doi: 10.1074/jbc.AC119.007981. Epub 2019 Apr 26.

Mass spectrometry-based molecular mapping of native FXIIIa cross-links in insoluble fibrin clots.

Author information

1
From the Departments of Biochemistry and Molecular Genetics and.
2
Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado 80045 and.
3
Laboratory of Proteomics Research, Biological Research Center of the Hungarian Academy of Sciences, H-6701 Szeged, Hungary.
4
From the Departments of Biochemistry and Molecular Genetics and kirk.hansen@ucdenver.edu.

Abstract

The roles of factor XIIIa-specific cross-links in thrombus formation, regression, or probability for embolization are largely unknown. A molecular understanding of fibrin architecture at the level of these cross-links could inform the development of therapeutic strategies to prevent the sequelae of thromboembolism. Here, we present an MS-based method to map native factor XIIIa cross-links in the insoluble matrix component of whole-blood or plasma-fibrin clots and in in vivo thrombi. Using a chaotrope-insoluble digestion method and quantitative cross-linking MS, we identified the previously mapped fibrinogen peptides that are responsible for covalent D-dimer association, as well as dozens of novel cross-links in the αC region of fibrinogen α. Our findings expand the known native cross-linked species from one to over 100 and suggest distinct antiparallel registries for interprotofibril association and covalent attachment of serpins that regulate clot dissolution.

KEYWORDS:

chemical digestion; factor XIII; fibrin; fibrinolysis; mass spectrometry (MS); protein cross-linking; thrombosis; transglutaminase

PMID:
31028172
PMCID:
PMC6552431
[Available on 2020-05-31]
DOI:
10.1074/jbc.AC119.007981

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