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1                                              FVa is homologous to FVIIIa, the cofactor for the FIXa p
2                                              FVa is known to effect a major conformational change to
3  FVa709 (des710-1545), FVa699 (des700-1545), FVa(692 (des693-1545), FVa678 (des679-1545), and FVa658
4              Tightly associated factor V(a) (FVa) and factor X(a) (FXa) serve as the essential prothr
5 c region, which is retained in FXa-activated FVa and platelet FVa.
6 S (C6PS) triggers assembly of a fully active FVa-FXa complex in solution and (2) that 2 molecules of
7                                 In addition, FVa is a target for proteolytic inactivation by activate
8 membrane dependence of FXa for high affinity FVa binding.
9 oop on APC of residues 306 to 314 defines an FVa binding site and accounts for much of the difference
10 in this loop in interactions between APC and FVa.
11 romboplastin time (APTT) clotting assays and FVa inactivation assays.
12 rhFVIII inactivation by rAPC by 6.4-fold and FVa inactivation by twofold, whereas membrane-bound FV s
13             Our data suggest that (1) FV and FVa are the physiologically significant substrates for A
14 ive site-labeled with Oregon Green to FV and FVa in the presence of phospholipids is approximately 5,
15 th 5-fluorescein ([5F]FFR-NotD) binds FV and FVa with remarkably high affinity in the absence of phos
16 d that the Arg(306) cleavage sites of FV and FVa(IIa) are distinct substrates for APC.
17 urprisingly modest decrease in bound FXa and FVa with little impact on fibrin formation.
18 s demonstrate that the dimerization site and FVa-binding site are both located in the catalytic domai
19                                      Because FVa heavy chain binds 2 molecules of C6PS, we conclude t
20 to promote high affinity association between FVa and FXa.
21 -1 bind FV-1033 with K(d) ~36-48 nM and bind FVa with K(d) ~252-456 nM.
22 idues 142-153) has been hypothesized to bind FVa.
23 leted FV (FV-1033) with K(d) ~9 nM and binds FVa with K(d) ~100 nM.
24                               Although bound FVa and FXa may have been present on the platelet core a
25 ; second, the inactivation of membrane-bound FVa by APC; and third, the proteolytic inactivation of m
26 litating factor Xa binding to membrane-bound FVa.
27 ysis, demonstrating allosteric regulation by FVa.
28 g site expression, whereas ADP is inert; (c) FVa does not compete with FVIIIa or FVIII for functional
29 raction, we expressed and purified two-chain FVa derivatives that were intracellularly truncated at t
30 nsisting of serine protease FXa and cofactor FVa, anchored to anionic phospholipids on the surface of
31 anisms are activated to produce its cofactor FVa, FXa(I16L) is driven to the protease state and resto
32  B-domain converts it to an active cofactor (FVa) for factor Xa (FXa).
33 e Factor (F) Xa complexed with its cofactor, FVa.
34  phosphoserine present in the plasma-derived FVa heavy chain and was resistant to phosphorylation at
35 ed inactivation than purified plasma-derived FVa on the thrombin-activated platelet surface.
36 dentical to that of purified, plasma-derived FVa.
37  allows distinction between platelet-derived FVa and FVaLeiden subsequent to APC-catalyzed cleavage w
38  chain subunit of purified, platelet-derived FVa contained only a fraction ( approximately 10-15%) of
39 analyses of the APC-cleaved platelet-derived FVa from FW showed a wild-type phenotype, despite the pr
40 duced cleavage, analyses of platelet-derived FVa from JMW demonstrated both normal FVa and FVaLeiden
41                             Platelet-derived FVa released from thrombin-activated platelets from a no
42                   Purified, platelet-derived FVa was 2-3-fold more resistant to activated protein C-c
43 ed origin of the secretable platelet-derived FVa.
44 ma origin of her secretable platelet-derived FVa.
45 ctivity exhibited by native platelet-derived FVa.
46 shed work, these results define an extensive FVa binding site in the positive exosite of APC that is
47  membranes, the affinity of [5F]FFR-NotD for FVa is similar, but increased approximately 55-fold for
48 f FV to APC, advance our understanding of FV/FVa regulation, and establish a mechanistic framework fo
49 w that TFPI-2 is associated with platelet FV/FVa.
50  them, including factors IXa (FIXa), FXa/FX, FVa, FVIII, prothrombin, and PS-sensitive marker Annexin
51 rine (C6PS), binds to discrete sites on FXa, FVa, and prothrombin to alter their conformations, to pr
52 nd the structure of the FXa dimer or the FXa-FVa complex.
53  directly inhibits thrombin generated by FXa/FVa (prothrombinase complex).
54 n a "common" pathway at the level of the FXa/FVa (prothrombinase) complex.
55 e, 0.30 +/- 0.05 and 0.19 +/- 0.04, when FXa/FVa is 1:4, with an increasing FXa and substrate concent
56 n, including prothrombinase (factor Xa [FXa]/FVa), the catalytic complex that directly generates thro
57  PS on their cell membranes, thus generating FVa and FXa binding sites and mediating the formation of
58 assays and APTT assays using purified Gln506-FVa and plasma containing Gln506-FV, it appeared that th
59                       Surprisingly, however, FVa(658) exhibited essentially normal kinetic parameters
60 ctivation by alpha-thrombin, factor Va(IIa) (FVa(IIa)).
61 ly contribute to APC cleavage at Arg(506) in FVa and play a small role in the interaction of APC with
62 study the effects of individual cleavages in FVa by APC and the importance of regions near the cleava
63 avage rates at the 2 major cleavage sites in FVa.
64 eavage at Arg(506) and were inactivated like FVa.
65  active and functions in prothrombinase like FVa.
66 ssays and in prothrombinase assays measuring FVa residual activity, in agreement with studies of puri
67             A mixture of 50 nM FXa and 50 nM FVa in the presence of 400 muM C6PS yielded both Xa homo
68 erived FVa from JMW demonstrated both normal FVa and FVaLeiden consistent with a plasma-derived origi
69 thesis that efficient inactivation of normal FVa by APC requires cleavage at R306.
70 yzed cleavage and inactivation of FV but not FVa(IIa) at position Arg(306) and that the Arg(306) clea
71                                     The NotD.FVa.membrane complex activates ProT with K(m)((app)) sim
72 activity of FXa and the cofactor activity of FVa.
73  with functional assays, similar analyses of FVa(IIa), derived from those FV species, revealed near-i
74 ions, we investigate the membrane binding of FVa and identify the key mechanisms that govern its inte
75 d ability to enhance APC-induced cleavage of FVa Arg306.
76 ants were primarily impaired for cleavage of FVa at Arg506.
77  mM Ca(2+) to show that the apparent K(d) of FVa-FXa interaction increased with an increase in FXa co
78  of site-specific fluorescent derivatives of FVa and FXa after laser injury in the mouse cremaster ar
79 isplaces a large portion of the A2 domain of FVa and projects the 654VKCIPDDDEDSYEIFEP670 segment as
80 main of APC engages R506 in the A2 domain of FVa through electrostatic interactions between positivel
81 ate the complex membrane binding dynamics of FVa and provide important insights into the molecular me
82 ge site for normal efficient inactivation of FVa by APC and supports other studies suggesting that re
83 rs essential for significant inactivation of FVa by APC.
84 nalyses of the APC-catalyzed inactivation of FVa(IIa) in an assay consisting of purified components i
85  and characterized for their inactivation of FVa.
86 further find that the domain organization of FVa deviates (sometimes significantly) from its crystall
87 is lost upon removal of the acidic region of FVa by thrombin.
88 c electron microscopy (cryo-EM) structure of FVa has revealed the arrangement of its A1-A2-A3-C1-C2 d
89 oop of APC and an electronegative surface of FVa.
90 olved in binding and cleaving at Arg(506) on FVa.
91                                     Based on FVa inactivation assays and APTT assays using purified G
92 rothrombinase complex by synthetic peptides, FVa residues 493-506 were proposed as a FXa binding site
93 ein C by thrombin and inactivation of plasma FVa by APC are not impaired during moderate hyperhomocys
94 s retained in FXa-activated FVa and platelet FVa.
95 with studies of purified plasma-derived Q506-FVa.
96 mparable with plasma-derived and recombinant FVa.
97 S binding exposes K(351) (part of a reported FVa binding region), K(242) (adjacent to the catalytic t
98                                 NotD reports FVa and not FV binding by a 3-fold increase in tripeptid
99 lu-Gly-Arg-chloromethyl ketone fully rescued FVa binding.
100 lpha-thrombin, the addition of the resulting FVa(IIa) to the plasma-based APC sensitivity assay produ
101  and R506 provide FXa-binding sites and that FVa cleaved at only R506 retains partial activity.
102                  To test the hypothesis that FVa residues 499-505 contribute to FXa binding, we creat
103                      Our results reveal that FVa can either adopt an upright or a tilted molecular or
104 idly than activity was lost, suggesting that FVa cleaved at only R506 is partially active.
105 interactions in the coagulation cascade, the FVa-APC interaction has long posed a challenge to struct
106 05 contribute to FXa binding, we created the FVa loop swap mutant (designated 499-505(VIII) FV) with
107 n an updated three-dimensional model for the FVa structure, residues 499-505, along with Arg-506, Arg
108  suggest that this A2 domain sequence of the FVa and FVIIIa cofactors evolved to have different speci
109 prothrombin and the C-terminal region of the FVa heavy chain do not contribute in a detectable way to
110 Here, we report the cryo-EM structure of the FVa-APC complex at 3.15 angstrom resolution in which the
111                 The cryo-EM structure of the FVa-APC complex validates the bulk of existing biochemic
112 ormed prothrombinase complex containing this FVa mutant had fairly normal kinetic parameters (k(cat)
113 surements and spectroscopic titrations, this FVa loop swap mutant had significantly reduced affinity
114  an inactive procofactor and is activated to FVa by proteolytic removal of a large inhibitory B-domai
115 the prothrombinase complex once activated to FVa.
116 ion and (2) that 2 molecules of C6PS bind to FVa light chain with one occupying a site in the C2 doma
117 ether dimerization of FXa and its binding to FVa in the presence of C6PS are competitive processes.
118 s that play a significant role in binding to FVa.
119 was decreased ~10-fold when FXa was bound to FVa in prothrombinase and a further ~3-4-fold when plasm
120 Xa-I16T), was greatly enhanced when bound to FVa membranes.
121 .Va heterodimers, but no FXa dimers bound to FVa.
122 APC inactivation of FV is slower compared to FVa, although proteolysis occurs at the same sites (Arg(
123 dues made significant minor contributions to FVa interactions: Lys(191), Lys(192), Asp(214), and Glu(
124 entified that provide major contributions to FVa interactions: Lys(193), Arg(229), and Arg(230).
125 , and FVIIIa residues 555-561 (homologous to FVa residues 499-506) are recognized as a FIXa binding s
126 s show that high affinity binding of NotD to FVa is membrane-independent, unlike the strict membrane
127 ing process and characteristics, specific to FVa or common among other membrane proteins, in concert
128                                       Unlike FVa, FV-short binds with high affinity (K(d) ~1 nM) to T
129  that both glycosidase-treated and untreated FVa(IIa) expressed identical cofactor activities and wer
130                    In a purified assay using FVa R506Q/R679Q, purified protein S D95A was shown to ha
131 ion of factor V (FV) and activated factor V (FVa).
132 in in the presence and absence of factor Va (FVa) and 5.0 x 10(-5) M phospholipid vesicles are slight
133 nt pathway, where it enhances the factor Va (FVa) and factor VIIIa (FVIIIa) inactivating property of
134 tion of the coagulation cofactors factor Va (FVa) and factor VIIIa.
135 n of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme acti
136 vated protein C (APC) cleavage of Factor Va (FVa) at residues R506 and R306 correlates with its inact
137 quence reported to interfere with factor Va (FVa) binding.
138  factor V (FV) upon activation to factor Va (FVa) by thrombin.
139 teraction of factor Xa (FXa) with factor Va (FVa) forms prothrombinase and drives thrombin formation
140                       Coagulation factor Va (FVa) is a large protein whose membrane interactions are
141                       Coagulation factor Va (FVa) is the cofactor component of the prothrombinase com
142 hrombotic effects by inactivating factor Va (FVa) on nearby endothelial surfaces.
143      Platelet- and plasma-derived factor Va (FVa) serve essential cofactor roles in prothrombinase-ca
144                                   Factor Va (FVa), derived from plasma or released from stimulated pl
145 used by decreased inactivation of factor Va (FVa).
146 ), inactivates blood coagulation factors Va (FVa) and VIIIa.
147 tially regulate APC recognition of FV versus FVa and uncover how FV-short can be protected from this
148 activated protein C (APC), the 499-505(VIII) FVa mutant was inactivated entirely normally by APC.
149 ed dimerization (K(d) ~ 147 nM) and weakened FVa binding (apparent K(d) values of 58, 92, and 128 nM
150                                         When FVa residual activity was measured after long exposure t
151 ane bindings of systems containing the whole FVa molecule.
152  neither dimerized nor formed a complex with FVa in the presence of 400 muM C6PS and 5 mM Ca(2+).
153 int to solvent, without making contacts with FVa.
154 1.6 +/- 0.3, when FXa is in a 1:1 ratio with FVa but becomes increasingly inverse, 0.30 +/- 0.05 and
155 at 5, 20, and 50 nM FXa while titrating with FVa in the presence of 400 muM C6PS and 3 or 5 mM Ca(2+)

 
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