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dc.contributor.authorChun, Haarin
dc.contributor.authorKurasawa, James H
dc.contributor.authorOlivares, Philip
dc.contributor.authorMarakasova, Ekaterina S
dc.contributor.authorShestopal, Svetlana A
dc.contributor.authorHassink, Gabriela U
dc.contributor.authorKarnaukhova, Elena
dc.contributor.authorMigliorini, Mary
dc.contributor.authorObi, Juliet O
dc.contributor.authorSmith, Ally K
dc.contributor.authorWintrode, Patrick L
dc.contributor.authorDurai, Prasannavenkatesh
dc.contributor.authorPark, Keunwan
dc.contributor.authorDeredge, Daniel
dc.contributor.authorStrickland, Dudley K
dc.contributor.authorSarafanov, Andrey G
dc.date.accessioned2022-08-15T13:15:29Z
dc.date.available2022-08-15T13:15:29Z
dc.date.issued2022-07-10
dc.identifier.urihttp://hdl.handle.net/10713/19571
dc.description.abstractBackground: Deficiency in blood coagulation factor VIII (FVIII) results in life-threating bleeding (hemophilia A) treated by infusions of FVIII concentrates. To improve disease treatment, FVIII has been modified to increase its plasma half-life, which requires understanding mechanisms of FVIII catabolism. An important catabolic actor is hepatic low density lipoprotein receptor-related protein 1 (LRP1), which also regulates many other clinically significant processes. Previous studies showed complexity of FVIII site for binding LRP1. Objectives: To characterize binding sites between FVIII and LRP1 and suggest a model of the interaction. Methods: A series of recombinant ligand-binding complement-type repeat (CR) fragments of LRP1 including mutated variants was generated in a baculovirus system and tested for FVIII interaction using surface plasmon resonance, tissue culture model, hydrogen–deuterium exchange mass spectrometry, and in silico. Results: Multiple CR doublets within LRP1 clusters II and IV were identified as alternative FVIII-binding sites. These interactions follow the canonical binding mode providing major binding energy, and additional weak interactions are contributed by adjacent CR domains. A representative CR doublet was shown to have multiple contact sites on FVIII. Conclusions: FVIII and LRP1 interact via formation of multiple complex contacts involving both canonical and non-canonical binding combinations. We propose that FVIII-LRP1 interaction occurs via switching such alternative binding combinations in a dynamic mode, and that this mechanism is relevant to other ligand interactions of the low-density lipoprotein receptor family members including LRP1. © 2022 The Authors.en_US
dc.description.urihttps://doi.org/10.1111/jth.15817en_US
dc.language.isoenen_US
dc.publisherWiley-Blackwellen_US
dc.relation.ispartofJournal of Thrombosis and Haemostasis : JTHen_US
dc.rights© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.en_US
dc.subjectLDL-receptor related protein-associated proteinen_US
dc.subjectblood coagulationen_US
dc.subjectfactor VIIIen_US
dc.subjecthemophilia Aen_US
dc.subjectlow density lipoprotein receptoren_US
dc.subjectlow density lipoprotein receptor-related protein 1en_US
dc.titleCharacterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts.en_US
dc.typeArticleen_US
dc.identifier.doi10.1111/jth.15817
dc.identifier.pmid35810466
dc.source.journaltitleJournal of thrombosis and haemostasis : JTH
dc.source.countryEngland


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