Cellular uptake of coagulation factor VIII: Elusive role of the membrane-binding spikes in the C1 domain

Castro-Núñez, Lydia; Koornneef, Johanna M.; Rondaij, Mariska G.; Bloem, Esther; Zwaan, Carmen van der; Mertens, Koen; Meijer, Alexander B.; Meems, Henriet

doi:10.1016/j.biocel.2017.05.027

Cited by 5 publications

(5 citation statements)

References 45 publications

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“…Our results indicate a major role of cluster II based on its higher affinity to FVIII and stronger inhibition of FVIII internalization in tissue culture. Notably, due to the more distant location of cluster II from the transmembrane region of LRP1 and flexibility of the molecule, cluster II has a higher capacity to spatially probe pre‐concentrated FVIII on cell membranes 20 and heparan sulfate proteoglycans. 21 However, our results are in contrast to data of Young et al, 46 who showed that cluster IV represents the major FVIII binding site, possibly due to difference in experimental conditions, in particular using recombinant protein expression ensured the protein folding by co‐expressing RAP in our study.…”

Section: Discussionmentioning

confidence: 99%

“… 7 , 9 , 15 , 16 , 17 , 18 , 19 In a pathway with direct FVIII–LRP1 interaction, it occurs via a small FVIII fraction (~5%) unbound to VWF and preconcentrated on cell surfaces. 20 , 21 , 22 In FVIII clearance, LRP1 acts in concert with the hepatic low density lipoprotein receptor (LDLR). 5 Both belong to the LDLR family of endocytic receptors 23 , 24 , 25 , 26 associated with many processes with clinical significance.…”

Section: Introductionmentioning

confidence: 99%

“…Plasma clearance of FVIII involves several receptors 5–14 with hepatic low density lipoprotein receptor‐related protein 1 (LRP1) playing a major role 7,9,15–19 . In a pathway with direct FVIII–LRP1 interaction, it occurs via a small FVIII fraction (~5%) unbound to VWF and preconcentrated on cell surfaces 20–22 . In FVIII clearance, LRP1 acts in concert with the hepatic low density lipoprotein receptor (LDLR) 5 .…”

Section: Introductionmentioning

confidence: 99%

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Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Chun

Kurasawa

Olivares

et al. 2022

Journal of Thrombosis and Haemostasis

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Background 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Chun

Kurasawa

Olivares

et al. 2022

Journal of Thrombosis and Haemostasis

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“…In addition to the interaction with LRP-1, FVIII requires prior binding to other structural elements on the cell surface to mediate the internalization by the cells. 11,12 These findings indicate that LRP-1 may serve as a co-receptor for multiple primary receptors, and multiple ligands.…”

Section: Letters To the Editormentioning

confidence: 95%

Endocytosis by macrophages: interplay of macrophage scavenger receptor-1 and LDL receptor-related protein-1

et al. 2019

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Multiple receptors may mediate the cellular uptake of a single protein and thereby affect the plasma level of the involved protein. In case of Von Willebrand factor (VWF) these receptors include LDL receptor-related protein-1 (LRP-1), Macrophage scavenger receptor-1 (MSR-1, SR-AI or CD204), the Macrophage Galactose-type lectin (CLEC10A, MGL or CD301), Siglec-5 and the Asialoglycoprotein receptor (ASGPR). 1 In the present study, we aimed to gain insight into the interplay of multiple receptors to the cellular internalization of a single ligand like VWF. The macrophages in the liver and spleen have been reported to contribute considerably to the cellular uptake of VWF. 2-4 Previously, we have shown that also human monocyte-derived macrophages (MDM) internalize VWF via a mechanism that depends on LRP-1. 5 We now analyzed the cell surface proteome of MDM using mass haematologica 2020; 105:e133

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“…In particular, FVIII has extremely low plasma concentration (≤1 nM) [56], insufficient for its effective interaction with LRP1 (K D ~20 nM). The involvement of HSPGs, abundantly expressed on cells [17], altogether with the cell membrane interaction of FVIII [57], is believed to increase its local concentration and facilitate LRP1 binding to LRP1. Similarly, HSPGs may facilitate FVIII interactions with other clearance receptors.…”

Section: Cell-surface Heparan-sulfate Proteoglycans (Hspgs)mentioning

confidence: 99%

Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice

Sarafanov

2023

IJMS

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Factor VIII (FVIII) is an important component of blood coagulation as its congenital deficiency results in life-threatening bleeding. Current prophylactic therapy of the disease (hemophilia A) is based on 3–4 intravenous infusions of therapeutic FVIII per week. This poses a burden on patients, demanding reduction of infusion frequency by using FVIII with extended plasma half-life (EHL). Development of these products requires understanding FVIII plasma clearance mechanisms. This paper overviews (i) an up-to-date state of the research in this field and (ii) current EHL FVIII products, including recently approved efanesoctocog alfa, for which the plasma half-life exceeds a biochemical barrier posed by von Willebrand factor, complexed with FVIII in plasma, which results in ~1 per week infusion frequency. We focus on the EHL FVIII products’ structure and function, in particular related to the known discrepancy in results of one-stage clotting (OC) and chromogenic substrate (CS) assays used to assign the products’ potency, dosing, and for clinical monitoring in plasma. We suggest a possible root cause of these assays’ discrepancy that is also pertinent to EHL factor IX variants used to treat hemophilia B. Finally, we discuss approaches in designing future EHL FVIII variants, including those to be used for hemophilia A gene therapy.

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Cellular uptake of coagulation factor VIII: Elusive role of the membrane-binding spikes in the C1 domain

Cited by 5 publications

References 45 publications

Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Characterization of interaction between blood coagulation factor VIII and LRP1 suggests dynamic binding by alternating complex contacts

Endocytosis by macrophages: interplay of macrophage scavenger receptor-1 and LDL receptor-related protein-1

Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice

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