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The apexes of these three loops within the C2 domain, are able to create a deep groove lined by hydrophobic (Trp31, Met83) and polar residues (Gln48, Ser78), as seen and consisting the "Open Form" of FVa-C2. This groove is seen as the primary membrane-binding site of the C2-Domain. ^[1] Link to Function.. maybe?

A second dimeric crystal form of FVa-C2, packed through the free edges of S6 strands, presenting a different Leu104-Val109 loop, suggesting capabilities of adopting a "Closed Form". In contrast to the "Open Form" of FVa-C2; when looking at the loops 1 and 3 are tilted towards the interior of the groove. This change is considered due to a twist around Gly28 cause it to be deformed (pseudo). In general there is a narrowing of the entrance to the shallow inner loop groove, particularly the critical Gln48 carboxamide; Took place due form the concerted tilting/ "twisting" of the main chain atoms, shifting up to ~7Å and a 12Å displacement of the Trp27 moiety → shifting closer to the other two loops. Once shifted closer, the groove seen in the Open Form is covered by a hydrophobic ridge of Trp27, Trp27 and Leu79, and now in the Closed Form with a smaller, 370Å hydrophobic surface compared to 520Å. ^[1]
Gln48 is crutial for some kind of actions of the entire Protein. ~Different colour, then link it to the Function Section.
The three loops are described by Macedo-Ribeiro et al. to protrude like spikes from the bottom of the barrel in monomeric FVa-C2.^[1] It is also worth noting that spike (1) & spike (3) are separated by β-hairpin structures and spike (2) is described as a wider irregularly loop comparatively. These three loops extending from the C2 domain, are all linked to each other, and to three shorter loops by an intricate H-bonding network which extends to residues at the bottom of the β-barrel.^[1]
The overall Barrel structure is closed at the top and bottom by three and two straight segments, giving it an overall spherical shape with a flattened upper surface.

Functionality of Human Coagulation Factor V (FV), as most proteins is strongly correlated to the conformation of the overall strcture. As noted above in the structural section, two structural forms of Human Coagulation Factor V were crystallized. These two structures were disctinct from each other based on a conformational change present in the C2 domain, alternating between Open and Closed. This change from close to open by exposing this groove results due to the kind of environment Human Coagulation Factor V finds itself in, and ultimately the source of it's function. This confers that FV is not an enzymatically active protein, but instead acts a cofactor part of the larger Cougulation Cascade (Ref Wiki).

The role of Human Coagulation Factor V, is act as a cofactor, enhances the ability of factor Xa to generate from prothrombin once activated (Fva). It is known that FV is activated in a positive feedback mechanism by α-thrombin and aided in conjunction with Human Coagulation Factor Xa, and inhibited by Active Protein C (1aut). Originally, the activation of FV to Fva was understood to require the exision of B segment between between the heavy and light chain at Arg-1018 and Arg-1545. The peptide as a whole remains united via the disulfide linkage connecting the N and C Terminus and interactions with calcium ions. ^[2] In 1999, the crystalization of FV in both Fv and Fva was identified prodividing further insight into the quaternary structure of FV and the underlining mechanism by which the protein functions. ^[1] This mechanism proposed has three novel points, which were over-looked based on assumed knowledge from previous studies modeling the mechanism for FV after the well characterized mechanism of vitamin K-dependent Coagulation Factors; VII (1dan) , IX (1pfx) , X (1c5m) and Protein C ^{[3] [4]}
The Mechanism Proposed ^[1] differs from the previous work, showing Ca²⁺-Independent stereospecific binding to phospholipid membranes, based on;
(1) Immersion of Hydrophobic residues at the apecis of loops in apolar membrane core.
(2) Specific Interactions with phosphatidylserine head groups in the groove enclosed by these loops.
(3) Favourable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.
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Some of the bold sections in this are potential green links

Detailed Proposed Mechanism ^[1]

For stereospecific and cooperative association with (P_ʟS)-rich membranes.
(1) FVa, with C2 domain in its closed form, approaches acidic membranes directed by protein-membrane electrostatic interactions.
(2) One or two (P_ʟS) molecules bind to anchoring points Arg150 or Gln48 in small groove of closed from → triggers widening of the groove and conversion to the open form.
(3) [(Fig. 5a.)]–A (P_ʟS) molecule occupies the opened specificity pocket.
(4) Now the unfolded hydrophobic spikes, perforate the polar membrane surface; Trp26, Trp27 and Leu79 side are immersed into the apolar core.
(5) Bottom of β-Barrel contacts negatively charged phosphate head groups on the membrane through favourable ionic interactions with basic residues located in the spikes and neighboring loops. ^{[5] [6]}

The C2 domain of FVa is essential for binding to phosphatidyl-ʟ-serine (P_ʟS). This is because the spikes and neighboring loops are highly connected and several continuous P_ʟS molecules would be necessary for association with spike unfolding and membrane insertion for a cooperative mechanism. This assures FVa-C2 binds only to cell membranes with the concentration of P_ʟS exceeding a critical threshold level and therefore selectively target FVa to procoagulated, P_ʟS-rich surfaces.

Experimental Evidence

Binding of FVa to a few acidic, lipid-specific sites results in substantial protein conformational changes. ^[1]

• A3 Domain interacts with phosphatidyl-choline. ^[7]
• Contributions from hydrophobicity of the heavy chains; A1 and A2. ^[8]
• Speculation of further conformational changes as associated with membrane, where the C2 Domain rotates to bring spike 1 and the Trp-rich surface (flat and extended) covering the front-side of the β-Barrel in contact with the phospholipid membrane [(Fig. 5b.)]. ^[1]

Finer Crystallography Details

X-Ray Diffraction of the C2 Domain of Human Coagulation Factor V (1czv) ^[1]
Resolution Method:Structure Replacement
Resolution: 2.40Å

High: 2.40Å

Low: 8.00Å

Condition;

pH: 10.00

Temperature: 289.0K

Number of Crystals used: 1

Geometry: Unit Cell Length  : Angle

a= 86.52Å  : α= 90°

b= 70.54Å  : β= 90°

c= 60.58Å  : γ= 90°

Radiation Source: Rotating Anode
Wavelength OR Range: 1.5418Å
Detector Type: Image Plate

References

1. ↑ ^{1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14} Macedo-Ribeiro S, Bode W, Huber R, Quinn-Allen MA, Kim SW, Ortel TL, Bourenkov GP, Bartunik HD, Stubbs MT, Kane WH, Fuentes-Prior P. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature. 1999 Nov 25;402(6760):434-9. PMID:10586886 doi:10.1038/46594
2. ↑ ^{2.0 2.1} Kane WH, Ichinose A, Hagen FS, Davie EW. Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats. Biochemistry. 1987 Oct 6;26(20):6508-14. PMID:2827731
3. ↑ Stenflo J. Contributions of Gla and EGF-like domains to the function of vitamin K-dependent coagulation factors. Crit Rev Eukaryot Gene Expr. 1999;9(1):59-88. PMID:10200912
4. ↑ Zwaal RF, Comfurius P, Bevers EM. Lipid-protein interactions in blood coagulation. Biochim Biophys Acta. 1998 Nov 10;1376(3):433-53. PMID:9805008
5. ↑ Zwaal RF, Comfurius P, Bevers EM. Lipid-protein interactions in blood coagulation. Biochim Biophys Acta. 1998 Nov 10;1376(3):433-53. PMID:9805008
6. ↑ Gerads I, Govers-Riemslag JW, Tans G, Zwaal RF, Rosing J. Prothrombin activation on membranes with anionic lipids containing phosphate, sulfate, and/or carboxyl groups. Biochemistry. 1990 Aug 28;29(34):7967-74. PMID:2261453
7. ↑ Kalafatis M, Rand MD, Mann KG. Factor Va-membrane interaction is mediated by two regions located on the light chain of the cofactor. Biochemistry. 1994 Jan 18;33(2):486-93. PMID:8286378
8. ↑ Koppaka V, Talbot WF, Zhai X, Lentz BR. Roles of factor Va heavy and light chains in protein and lipid rearrangements associated with the formation of a bovine factor Va-membrane complex. Biophys J. 1997 Nov;73(5):2638-52. PMID:9370458 doi:10.1016/S0006-3495(97)78293-6