Sandbox Reserved 350: Difference between revisions
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Coagulation Factor V originally studied in 1987 by William H. Kane, Akitada Ichinose, Frederick S. Hagen and Earl W. Davie, out of University of Washington, Seattle. <ref name="Old">PMID: 2827731 </ref> | Coagulation Factor V originally studied in 1987 by William H. Kane, Akitada Ichinose, Frederick S. Hagen and Earl W. Davie, out of University of Washington, Seattle. <ref name="Old">PMID: 2827731 </ref> | ||
[http://en.wikipedia.org/wiki/Coagulation_cascade Coagulation] is a complex cascade of a biological reaction that takes place after an injury causing bleeding, to prevent bleeding; A step of hemostatsis, which | [http://en.wikipedia.org/wiki/Coagulation_cascade Coagulation] is a complex cascade of a biological reaction that takes place after an injury causing bleeding, to prevent bleeding; A step of hemostatsis, which facilitates the formation of fibrin. There approximately 30 known factors which play a role in this massive cascade response. A possible explanation for the sheer complexity associated with what is known about this cascade is that tight regulation for the formation of blood clots are crucial. | ||
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The role of Human Coagulation Factor V is to act as a cofactor along with Factor X and Prothrombin (Factor II, inactive) to form a [http://en.wikipedia.org/wiki/Prothrombinase Prothrombinase] complex activating Prothrobin to Thrombin (FIIa). Thrombin is then able to activate | The role of Human Coagulation Factor V is to act as a cofactor along with Factor X and Prothrombin (Factor II, inactive) to form a [http://en.wikipedia.org/wiki/Prothrombinase Prothrombinase] complex activating Prothrobin to Thrombin (FIIa). Thrombin is then able to activate Fibrinogen (Factor I) into Fibrin (FIa), which connects platelets bound at the site of injury; formation of a clot. | ||
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It is vital for | It is vital for controlled blood clot formation based on known human diseases/conditions of irregular clotting which are quiet devastating. Two clear aspects of blood clotting involve either under clotting or excessive clotting. The inability to form a clot leads to excessive bleeding from a minor abration known as [http://en.wikipedia.org/wiki/Haemophilia hemophila]. <ref name="Hemo">PMID: 21453683 </ref> [http://en.wikipedia.org/wiki/Thrombosis Thrombosis] is the second case, where excessive clotting or clotting when no wound is present results in free floating embolisms or thombuses. <ref name="Throm">PMID: 21455860 </ref> Floating free in the blood allows the thrombus to lodge itself within the circulatory system, interferring with orgran downstream of the circulating blood. Unusual blood circulation/clotting by a thrombus are causes of heart attacks, strokes and necrosis of tissue. <ref name="Throm2">PMID: 21359071 </ref> | ||
{{STRUCTURE_1czv|PDB=1czv|SCENE=}} | {{STRUCTURE_1czv|PDB=1czv|SCENE=}} | ||
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[[Image:3D Jellow B-Barrel Motif.png|thumb|left|upright=1.5|alt=Distorted Jelly-Roll β-barrel motif with three active loops. The β-barrel motif is labeled in red and the three loops in orange.|Secondary structure of C2 Domain of 1czv.]] | [[Image:3D Jellow B-Barrel Motif.png|thumb|left|upright=1.5|alt=Distorted Jelly-Roll β-barrel motif with three active loops. The β-barrel motif is labeled in red and the three loops in orange.|Secondary structure of C2 Domain of 1czv.]] | ||
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'''The FVa-C2''', which is classified as a ''' <font color='red'> distorted jelly-roll </font> ''' <scene name='Sandbox_Reserved_350/Expriment3/1'> β-barrel motif </scene>, is | '''The FVa-C2''', which is classified as a ''' <font color='red'> distorted jelly-roll </font> ''' <scene name='Sandbox_Reserved_350/Expriment3/1'> β-barrel motif </scene>, is composed of <scene name='Sandbox_Reserved_350/Expriment5/1'> eight major antiparallel strands </scene> arranged into two ''' <font color='lawngreen'> β-sheets of five </font> and <font color='maroon'> three strands </font> ''' packed against one another. | ||
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Salt bridges located within the "upper" segment ''' <font color='goldenrod'> (Asp61-Arg134) </font>. The C2-Domain of Human coagulation factor is homologous to a larger family of adhesion proteins; [http://proteopedia.org/wiki/index.php/Category:Discoidin_family Discoidin],but not related to synaptotagmin-like C2 domains.<ref name="Pubmed"/> | Salt bridges located within the "upper" segment ''' <font color='goldenrod'> (Asp61-Arg134) </font>. The C2-Domain of Human coagulation factor is homologous to a larger family of adhesion proteins; [http://proteopedia.org/wiki/index.php/Category:Discoidin_family Discoidin], but not related to synaptotagmin-like C2 domains.<ref name="Pubmed"/> | ||
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A second dimeric crystal form of FVa-C2, packed through the free edges of S6 strands, presenting a different Leu104-Val109 | A second dimeric crystal form of FVa-C2, packed through the free edges of S6 strands, presenting a different Leu104-Val109 | ||
loop, suggests 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; | loop, suggests 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; Taking place due form the concerted tilting/ "twisting" of the main chain atoms, shifting up to ~7Å and a 12Å displacement of the Trp27 moiety <big>→</big> 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. <ref name="Pubmed"/> | ||
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The three loops are described by ''Macedo-Ribeiro et al.'' to protrude like spikes from the bottom of the barrel in monomeric FVa-C2.<ref name="Pubmed"/> 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.<ref name="Pubmed"/> | The three loops are described by ''Macedo-Ribeiro et al.'' to protrude like spikes from the bottom of the barrel in monomeric FVa-C2.<ref name="Pubmed"/> 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.<ref name="Pubmed"/> | ||
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Functionality of Human Coagulation Factor V (FV), as most proteins is strongly correlated to the conformation of the overall | Functionality of Human Coagulation Factor V (FV), as most proteins is strongly correlated to the conformation of the overall structure. As noted above in the structural section, two structural forms of Human Coagulation Factor V C2 Domain were crystallized. These two structures were distinct from each other based on a conformational change present, alternating between what was described as a Open and Closed form. 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 its function. This confers that FV is not an enzymatically active protein, but instead acts a cofactor part of the larger [http://en.wikipedia.org/wiki/File:Coagulation_full.svg Coagulation Cascade.] | ||
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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 [http://en.wikipedia.org/wiki/Protein_C Active Protein C] [http://www.proteopedia.org/wiki/index.php/1aut (1aut)]. | 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 [http://en.wikipedia.org/wiki/Protein_C Active Protein C] [http://www.proteopedia.org/wiki/index.php/1aut (1aut)]. | ||
Originally, the activation of FV to Fva was understood to require the | Originally, the activation of FV to Fva was understood to require the excision of B segment 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. <ref name="Old"/> In 1999, the [[#Finer Crystallography Details| crystallization]] of FV in both Fv and Fva was identified providing further insight into the quaternary structure of FV and the underlining mechanism by which the protein functions. <ref name="Pubmed"/> 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 [http://en.wikipedia.org/wiki/Coagulation Coagulation Factors]; [http://en.wikipedia.org/wiki/Factor_VII VII] [http://proteopedia.org/wiki/index.php/1dan (1dan)] | ||
, [http://en.wikipedia.org/wiki/Factor_IX IX] [http://proteopedia.org/wiki/index.php/1pfx (1pfx)] | , [http://en.wikipedia.org/wiki/Factor_IX IX] [http://proteopedia.org/wiki/index.php/1pfx (1pfx)] | ||
, [http://en.wikipedia.org/wiki/Factor_X X] [http://proteopedia.org/wiki/index.php/1c5m (1c5m)] | , [http://en.wikipedia.org/wiki/Factor_X X] [http://proteopedia.org/wiki/index.php/1c5m (1c5m)] | ||
and Protein C <ref name="KA">PMID: 10200912</ref> | and Protein C <ref name="KA">PMID: 10200912</ref> | ||
<ref name="KB">PMID: 9805008 </ref> | <ref name="KB">PMID: 9805008 </ref> | ||
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The '''Mechanism Proposed''' <ref name="Pubmed"/> differs from the previous work, showing Ca<sup>2+</sup>-Independent stereospecific binding to phospholipid membranes, based on; | The '''Mechanism Proposed''' <ref name="Pubmed"/> differs from the previous work, showing Ca<sup>2+</sup>-Independent stereospecific binding to phospholipid membranes, based on; | ||
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'''(1)''' Immersion of Hydrophobic residues at the | '''(1)''' Immersion of Hydrophobic residues at the apices of loops in apolar membrane core. | ||
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'''(2)''' Specific Interactions with phosphatidylserine head groups in the groove enclosed by these loops. | '''(2)''' Specific Interactions with phosphatidylserine head groups in the groove enclosed by these loops. | ||
