An acquired factor V inhibitor associated with defective factor V function, storage and binding to multimerin 1

Jeimy, Samira; Krakow, Elizabeth F.; Fuller, Nola; Tasneem, Subia; Hayward, Catherine P.M.

doi:10.1111/j.1538-7836.2007.02860.x

Cited by 8 publications

(5 citation statements)

References 13 publications

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“…1) [4], compared to less striking reductions (< 55%) reductions for mutations at other C2 [4] and C1 domain residues. The more important role of the C2 domain binding site in MMRN1 binding is consistent with a recent report of an autoantibody against the FV C2 domain, associated with a transient platelet FV deficiency, that ablated FVa procoagulant function and FV-MMRN1 binding [15]. The homologous roles of the FV C1 and C2 domains in MMRN1 binding could be important for the normal costorage of FV and MMRN1 in platelets.…”

supporting

confidence: 90%

Location of the multimerin 1 binding site in coagulation factor V: An update

Jeimy

Quinn-Allen

Fuller

et al. 2008

Thrombosis Research

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Activated coagulation factor V (FVa) is an important cofactor that accelerates thrombin production. In human blood, 25% of the factor V (FV) is stored in platelets, complexed to the polymeric, FV binding protein multimerin 1 (MMRN1). The light chain of FV is required for MMRN1 binding, and its C2 domain contains a MMRN1 binding site that overlaps phospholipid binding residues essential for FVa procoagulant function. The homologous structures and roles of the FVa light chain C1 and C2 domains led us to investigate if the C1 domain also contains a MMRN1 binding site. The MMRN1 binding properties of FV constructs were tested by modified enzyme-linked immunoassays, before and after thrombin activation. The constructs tested included the combined C1 and C2 domain deleted FV, and B-domain deleted forms of FV containing C1 domain point mutations or combined C1 and C2 domain phospholipid binding site mutations. The MMRN1 binding site in FV/FVa was mapped to a large region that included the C1 domain phospholipid binding residues Y1956 and L1957. The FV construct with combined C1 and C2 domain phospholipid binding site mutations had no MMRN1 binding, highlighting the critical role of the FV C1 and C2 domain phospholipid binding residues in MMRN1 binding. Our data update the information on the structural features of FV and FVa important for MMRN1 binding, and suggest that the extended MMRN1 binding site in the C1 and C2 domains is important for the storage of FV-MMRN1 complexes in platelets.Activated FV (FVa) is a key coagulation cofactor that accelerates the production of thrombin by the prothrombinase complex [1]. In blood, approximately 25% of the factor V (FV) is retained in platelet α-granules, where FV is stored as a partially activated cofactor complexed to the polymeric protein multimerin 1 (MMRN1) [2,3]. In humans, MMRN1-FV binding is predominantly noncovalent, although 25% of platelet FV is disulfide linked to MMRN1 [3]. Noncovalent FV-MMRN1 binding involves an extended region of the FV light chain C2 domain, that overlaps the FVa membrane binding site [4]. Recently solved FVa crystal structures and mutagenesis studies of FV function have provided evidence that the C domains of FV use structurally similar features to promote FVa binding to phospholipid membranes [5][6][7][8]. Nonetheless, the functions of the FV C1 domain are not as well characterized as those of the C2 domain. The possibility that the C1 domain contributes to MMRN1 binding is supported by the absent MMRN1 binding of FV constructs lacking the entire light chain, compared to the impaired MMRN1 binding of FV constructs lacking only the C2 domain [4]. These observations led us to investigate a potential MMRN1 binding site in the FV C1 domain.

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supporting

confidence: 90%

Location of the multimerin 1 binding site in coagulation factor V: An update

Jeimy

Quinn-Allen

Fuller

et al. 2008

Thrombosis Research

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“…MMRN1 works as a significant part in the blood system. In platelets, MMRN1 acts as a binding protein for coagulation factor V (a key regulator of coagulation), affecting the function and storage of factor V [ 41 ]. Besides, Laszlo et al drew a point that MMRN1 could be used as a new marker to refine the risk stratification of pediatric acute myeloid leukemia [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Implications of Novel Gene Signatures in Gastric Cancer Microenvironment

et al. 2020

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“…TGA and mathematical simulations of thrombin generation indicate that reductions in FV prolong the lag phase and reduce total thrombin generation (13,15). TGA have also illustrated the effectsofacquired FV deficiency, due to antibodies that inhibitphospholipid and MMRN1 binding, and reduce plateletFVstorage (16).…”

Section: Introductionmentioning

confidence: 99%

Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation

Jeimy¹,

Fuller²,

Tasneem³

et al. 2008

Thromb Haemost

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Multimerin 1 (MMRN1) is a polymeric, factor V (FV) binding protein that is stored in platelet and endothelial cell secretion granules but is undetectable in normal plasma. In human platelet alpha-granules, FV is stored complexed to MMRN1, predominantly by noncovalent binding interactions. The FV binding site for MMRN1 is located in the light chain, where it overlaps the C1 and C2 domain membrane binding sites essential for activated FV (FVa) procoagulant function. Surface plasmon resonance (SPR), circular dichroism (CD) and thrombin generation assays were used to study the binding of FV and FVa to MMRN1, and the functional consequences. FV and FVa bound MMRN1 with high affinities (K(D): 2 and 7 nM, respectively). FV dissociated more slowly from MMRN1 than FVa in SPR experiments, and CD analyses suggested greater conformational changes in mixtures of FV and MMRN1 than in mixtures of FVa and MMRN1. SPR analyses indicated that soluble phosphatidylserine (1,2-Dicaproylsn-glycero-3-phospho-L-serine) competitively inhibited both FV-MMRN1 and FVa-MMRN1 binding. Furthermore, exogenous MMRN1 delayed and reduced thrombin generation by plasma and platelets, and it reduced thrombin generation by preformed FVa. Exogenous MMRN1 also delayed FV activation, triggered by adding tissue factor to plasma, or by adding purified thrombin or factor Xa to purified FV. The high affinity binding of FV to MMRN1 may facilitate the costorage of the two proteins in platelet alpha-granules. As a consequence, MMRN1 release during platelet activation may limit platelet dependent thrombin generation in vivo.

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An acquired factor V inhibitor associated with defective factor V function, storage and binding to multimerin 1

Cited by 8 publications

References 13 publications

Location of the multimerin 1 binding site in coagulation factor V: An update

Location of the multimerin 1 binding site in coagulation factor V: An update

Prognostic Implications of Novel Gene Signatures in Gastric Cancer Microenvironment

Multimerin 1 binds factor V and activated factor V with high affinity and inhibits thrombin generation

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