ArticleThe Journal of biological chemistry2013
Factor VIII C1 domain spikes 2092-2093 and 2158-2159 comprise regions that modulate cofactor function and cellular uptake.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- A combinatorial CAAR-T cell strategy to eliminate factor VIII inhibitors in preclinical models of hemophilia A.iScience · 2026Article
- Patient anti-FVIII drug antibodies bind preferentially to a subset of FVIII covalent states.Blood advances · 2025Article
- Structure of coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor.Blood · 2023Article
- Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts.Journal of thrombosis and haemostasis : JTH · 2022Article
- Isolated Variable Domains of an Antibody Can Assemble on Blood Coagulation Factor VIII into a Functional Fv-like Complex.International journal of molecular sciences · 2022Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- FVIII inhibitors display FV-neutralizing activity in the prothrombin time assay.Journal of thrombosis and haemostasis : JTH · 2021Article
- Structure of blood coagulation factor VIII in complex with an anti-C1 domain pathogenic antibody inhibitor.Blood · 2021Article
- Article
- Identification of Key Coagulation Activity Determining Elements in Canine Factor VIII.Molecular therapy. Methods & clinical development · 2020Article
- Interaction Between the a3 Region of Factor VIII and the TIL'E' Domains of the von Willebrand Factor.Biophysical journal · 2019Article
- Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products.Blood advances · 2019Article
- Molecular mechanisms of missense mutations that generate ectopic N-glycosylation sites in coagulation factor VIII.The Biochemical journal · 2018Article
- Factor VIII/V C-domain swaps reveal discrete C-domain roles in factor VIII function and intracellular trafficking.Haematologica · 2017Article
- The C1 and C2 domains of blood coagulation factor VIII mediate its endocytosis by dendritic cells.Haematologica · 2017Article
- Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1): IDENTIFICATION OF CLUSTER IV ON LRP1 AS THE MAJOR BINDING SITE.The Journal of biological chemistry · 2016Article
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- Molecular design and downstream processing of turoctocog alfa (NovoEight), a B-domain truncated factor VIII molecule.Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis · 2016Article
- Article
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9 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The C1 domain of factor VIII (FVIII) has been implicated in binding to multiple constituents, including phospholipids, von Willebrand factor, and low-density lipoprotein receptor-related protein (LRP). We have previously described a human monoclonal antibody called KM33 that blocks these interactions as well as cellular uptake by LRP-expressing cells. To unambiguously identify the apparent "hot spot" on FVIII to which this antibody binds, we have employed hydrogen-deuterium exchange mass spectrometry. The results showed that KM33 protects FVIII regions 2091-2104 and 2157-2162 from hydrogen-deuterium exchange. These comprise the two C1 domain spikes 2092-2093 and 2158-2159. Spike 2092-2093 has been demonstrated recently to contribute to assembly with lipid membranes with low phosphatidylserine (PS) content. Therefore, spike 2158-2159 might serve a similar role. This was assessed by replacement of Arg-2159 for Asn, which introduces a motif for N-linked glycosylation. Binding studies revealed that the purified, glycosylated R2159N variant had lost its interaction with antibody KM33 but retained substantial binding to von Willebrand factor and LRP. Cellular uptake of the R2159N variant was reduced both by LRP-expressing U87-MG cells and by human monocyte-derived dendritic cells. FVIII activity was virtually normal on membranes containing 15% PS but reduced at low PS content. These findings suggest that the C1 domain spikes 2092-2093 and 2158-2159 together modulate FVIII membrane assembly by a subtle, PS-dependent mechanism. These findings contribute evidence in favor of an increasingly important role of the C1 domain in FVIII biology.
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