Factor VIII Interacts with the Endocytic Receptor Low-density Lipoprotein Receptor-related Protein 1 via an Extended Surface Comprising “Hot-Spot” Lysine Residues

Biggelaar, Maartje van den; Madsen, Jesper J.; Faber, Johan H.; Zuurveld, Marleen; Zwaan, Carmen van der; Olsen, Ole H.; Stennicke, Henning R.; Mertens, Koen; Meijer, Alexander B.

doi:10.1074/jbc.m115.650911

Cited by 29 publications

(40 citation statements)

References 53 publications

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“…Further studies are necessary to determine whether any of these lysine residues are indeed critical for intact fVIII binding to full-length LRP1. Although our ionic strength dependence data suggest the involvement of at least two lysine residues in the interaction, the study of van den Biggelaar et al (31) did not identify any single pair of lysine residues that ablated binding when mutated, and the study concluded that fVIII interacts with LRP1 via an extended surface. This apparent discrepancy can be explained by the possibility that several lysine residues may compensate for one another.…”

Section: Discussioncontrasting

confidence: 82%

“…Binding to LRP1-Prior studies examined the binding of the fVIII light chain to cluster II of LRP1 and observed that chemical modification of lysine residues in the fVIII light chain abolished its binding to cluster II, suggesting that lysine residues are important for this binding interaction (31). To determine whether lysine residues are critical for the binding of the entire fVIII molecule to full-length LRP1, we performed a similar experiment by first coating B domain-deleted fVIII (BDD-fVIII) in microtiter wells.…”

Section: Chemical Modification Of Fviii Lysine Residues Abolishes Itsmentioning

confidence: 99%

“…Indeed, numerous studies have characterized the binding of fVIII to LRP1, although most studies (12)(13)(14)(15) have used fragments of these proteins, which do not give a clear picture of the molecular interactions involved. In the most comprehensive investigation, van den Biggelaar et al (31) utilized hydrogen-deuterium exchange mass spectrometry and mutational analysis to conclude that the interaction between the fVIII light chain and cluster II from LRP1 occurs over an extended surface containing multiple lysine residues.…”

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confidence: 99%

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Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1)

Young¹,

Migliorini

Strickland

2016

Journal of Biological Chemistry

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Hemophilia A is a bleeding disorder caused by a deficiency in coagulation factor VIII (fVIII) that affects 1 in 5,000 males. Current prophylactic replacement therapy, although effective, is difficult to maintain due to the cost and frequency of injections. Hepatic clearance of fVIII is mediated by the LDL receptor-related protein 1 (LRP1), a member of the LDL receptor family. Although it is well established that fVIII binds LRP1, the molecular details of this interaction are unclear as most of the studies have been performed using fragments of fVIII and LRP1. In the current investigation, we examine the binding of intact fVIII to full-length LRP1 to gain insight into the molecular interaction. Chemical modification studies confirm the requirement for lysine residues in the interaction of fVIII with LRP1. Examination of the ionic strength dependence of the interaction of fVIII with LRP1 resulted in a Debye-Hückel plot with a slope of 1.8 ± 0.5, suggesting the involvement of two critical charged residues in the interaction of fVIII with LRP1. Kinetic studies utilizing surface plasmon resonance techniques reveal that the high affinity of fVIII for LRP1 results from avidity effects mediated by the interactions of two sites in fVIII with complementary sites on LRP1 to form a bivalent fVIII·LRP1 complex. Furthermore, although fVIII bound avidly to soluble forms of clusters II and IV from LRP1, only soluble cluster IV competed with the binding of fVIII to full-length LRP1, revealing that cluster IV represents the major fVIII binding site in LRP1.

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Section: Discussioncontrasting

confidence: 82%

Section: Chemical Modification Of Fviii Lysine Residues Abolishes Itsmentioning

confidence: 99%

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confidence: 99%

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Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1)

Young¹,

Migliorini

Strickland

2016

Journal of Biological Chemistry

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“…For certain LRP1 ligands, such as fVIII, identification of lysine pairs that contribute to LRP1 binding might be beneficial, as fVIII is used as a clinical product to treat hemophilia, and delaying its LRP1-mediated hepatic clearance would likely generate a molecule with a longer circulating half-life. Using hydrogen deuterium exchange experiments along with mutational analysis and SPR binding analysis, van den Biggelaar et al (50) concluded that the interaction between fVIII and cluster II of LRP1 occurs over an extended surface composed of multiple lysine residues and that no individual lysine residues dominate the binding interaction. However, if fVIII follows the same trend as RAP D1D2 and RAP D3, then mutation of two or more critical lysine residues would be required to sufficiently reduce its affinity for LRP1.…”

Section: Discussionmentioning

confidence: 99%

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation

Prasad¹,

Young²,

Strickland

2016

Journal of Biological Chemistry

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The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain. Studies on the interaction of the RAP third domain with LRP1 reveal critical contributions by lysine 256 and lysine 270 for this interaction. From these studies, a model for ligand recognition by this class of receptors has been proposed. Here, we employed surface plasmon resonance to investigate the binding of RAP D1D2 to LRP1. Our results reveal that the high affinity of D1D2 for LRP1 results from avidity effects mediated by the simultaneous interactions of lysine 60 in D1 and lysine 191 in D2 with sites on LRP1 to form a bivalent D1D2-LRP1 complex. When lysine 60 and 191 are both mutated to alanine, the binding of D1D2 to LRP1 is ablated. Our data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor.The LDL receptor-related protein 1 (LRP1) is a member of the LDL receptor family and is a highly efficient endocytic and signal-transducing receptor that plays an important role in vascular development, lipoprotein metabolism, and inflammation (1-3). Originally identified as the hepatic receptor responsible for the removal of ␣ 2 -macroglobulin (␣ 2 M) 3 -protease complexes (4), we now know that LRP1 recognizes numerous ligands, including lipoproteins, matrix proteins, growth factors (1, 2, 5, 6), and extracellular proteases (7-11). Deletion of the Lrp1 gene in mice results in early embryonic lethality at E13.5 (12, 13) due to extensive hemorrhaging resulting from a failure to recruit and maintain vascular smooth muscle cells and pericytes in the vessels. Selective deletion of LRP1 in vascular smooth muscle cells (smLRP1 Ϫ/Ϫ mice) reveals that LRP1 protects against the development of atherosclerosis by attenuating PDGF receptor activation (14, 15) and prevents formation of aneurysms (11, 16) in part by regulating the levels of proteases that are known to degrade matrix components (11).The efficient delivery of LRP1 and certain other members of the LDL receptor family to the cell surface require their association with a 39-kDa protein termed the receptor-associated protein (RAP). RAP was initially identified when it co-purified with LRP1 (17,18). Subsequent work demonstrated that RAP binds tightly to LRP1 and prevents ligands from associating with this receptor (19,20). In the endoplasmic reticulum (ER), RAP functions a...

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“…High affinity binding seems to involve the interaction with two or more LBDs requiring at least two lysine residues located at an appropriated distance - 18-20 Å according to structural data – which allows the simultaneous binding of two consecutive LBDs [56]. Likewise, the relative contribution of a single lysine residue of a ligand protein to the interaction may be difficult to rationalize in terms of stereo-chemical properties and the overall binding affinity may be the result of the additive effect of various weak binding sites [61].…”

Section: Resultsmentioning

confidence: 99%

The low-density lipoprotein receptor-related protein-1 is essential for Dengue virus infection

Huerta

Martín

Sarría

et al. 2020

Preprint

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19Dengue virus (DENV) causes the most prevalent and rapidly spreading arboviral 20 disease of humans. It enters human cells by receptor-mediated endocytosis. Numerous 21 cell surface proteins have been proposed as DENV entry factors. Among these, the 99 Regulation of lipid metabolism influences significantly the efficiency of DENV infection 100 and replication in vitro e in vivo [25-28]. Sequence stretches on DENV E and capsid 101 proteins resemble receptor binding motifs of ApoE [29]. ApoE is present in many 102 lipoproteins and interacts with several receptors of the low-density lipoprotein receptor 103 (LDLR) family [30]. Bovine lactoferrin, partially inhibits DENV and Japanese encephalitis 104 infection presumably competing for binding to the LDLR [31,32]. Collectively, these 105 results have suggested that LDLR may be involved on DENV entry to target cells. Yet, 106 conclusive evidences of the participation of LDLR on DENV attachment and/or entry 107 have not been obtained. 108 The LDLR family comprises at least 13 separate cell receptors that mediate lipoprotein 109 internalization, although some also play a role in the regulation of cellular physiology 110 and intracellular signaling [33]. In the context of the early events of the DENV infectious 111 cycle we decided to focus our interest on a different member of the family, the LRP1 112 receptor. This protein plays a role not only in lipoprotein endocytosis but also in the 7 113 internalization of protease:serpin complexes and, particularly of activated alpha-2-114 macroglobulin (α2M*):protease complexes [34]. We have found that proteins 115 participating in these processes are significantly enriched within the plasma DENV 116 interactome [35,36]. Also we have shown that α2M*, a ligand of LRP1, directly binds 117 DENV virions and favors DENV infection [37]. 118

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Factor VIII Interacts with the Endocytic Receptor Low-density Lipoprotein Receptor-related Protein 1 via an Extended Surface Comprising “Hot-Spot” Lysine Residues

Cited by 29 publications

References 53 publications

Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1)

Evidence That Factor VIII Forms a Bivalent Complex with the Low Density Lipoprotein (LDL) Receptor-related Protein 1 (LRP1)

High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation

The low-density lipoprotein receptor-related protein-1 is essential for Dengue virus infection

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