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

Schmitt, Lauren R. and Henderson, Rachel and Barrett, Alexander and Darula, Zsuzsanna and Issaian, Aaron (2019) Mass spectrometry-based molecular mapping of native FXIIIa cross-links in insoluble fibrin clots. JOURNAL OF BIOLOGICAL CHEMISTRY, 294 (22). pp. 8773-8778. ISSN 0021-9258 (print); 1083-351X (online)

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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 C region of fibrinogen . 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.

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