Sandbox136: Difference between revisions

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=='''Introduction'''==
 
== '''Introduction''' ==




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Anum-II has a length of 134 amino-acids. The phospholipase is formed by a short N-terminalαhelix (between residues 2-12), a 2nd αhelix (residues 40-55), two-stranded antiparallel <scene name='Sandbox136/sheet/1'>feuillets</scene> linked thanks to a βwing (74-85) and a 3rd αhelix (residues 90-107). The 3rd αhelix is bound to the 2nd αhelix (in an antiparallele way) thanks to disulfure bonds ([Cys 44-Cys 105] and [Cys 51-Cys 98]) and thus form a <scene name='Sandbox136/Stabilisation/1'>rigid platform</scene>. The protein is stabilized by 5 other disulfides bonds [Cys 27-Cys 125], [Cys 29-Cys 45] [Cys 50 Cys 134] [Cys 61-Cys 91] [Cys84-Cys96]. Alignment of Anum-II with other PLA2 have revealed that the positions of amino-acid residues which form the catalytic apparatus are conserved (His48,Tyr52, Tyr73 and Asp99) except for Asp49 which is replaced by Lys 49.  
Anum-II has a length of 134 amino-acids. The phospholipase is formed by a short N-terminalαhelix (between residues 2-12), a 2nd αhelix (residues 40-55), two-stranded antiparallel <scene name='Sandbox136/Feuillets/1'>sheet</scene> linked thanks to a βwing (74-85) and a 3rd αhelix (residues 90-107). The 3rd αhelix is bound to the 2nd αhelix (in an antiparallele way) thanks to disulfure bonds ([Cys 44-Cys 105] and [Cys 51-Cys 98]) and thus form a <scene name='Sandbox136/Stabilisation/1'>rigid platform</scene>. The protein is stabilized by 5 other disulfides bonds [Cys 27-Cys 125], [Cys 29-Cys 45] [Cys 50 Cys 134] [Cys 61-Cys 91] [Cys84-Cys96]. Alignment of Anum-II with other PLA2 have revealed that the positions of amino-acid residues which form the catalytic apparatus are conserved (His48,Tyr52, Tyr73 and Asp99) except for Asp49 which is replaced by Lys 49.  
The structure of the protein has revealed the presence of an anion-binding site between <scene name='Sandbox136/Anion/2'>R34</scene>, <scene name='Sandbox136/Anion/2'>K53</scene>  and a water molecule. Sulfate ion is anchored thanks to hydrogen bonds between:
The structure of the protein has revealed the presence of an anion-binding site between <scene name='Sandbox136/Anion/2'>R34</scene>, <scene name='Sandbox136/Anion/2'>K53</scene>  and a water molecule. Sulfate ion is anchored thanks to hydrogen bonds between:


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Lys49 PLA2 has a strong myotoxicitic effect. The replacement of Asp49 by <scene name='Sandbox136/Lys_49/1'>Lys49</scene> provides a particular role of the protein. Indeed, Asp49 allows the binding of Ca2+ an essential co-factor which is responsible for the activation of the catalytically apparatus (thanks to conserved amino-acids:His48, Tyr52, Tyr73 and Asp99). Lys49 PLA2 is not able to bind the co-factor, and thus is catalytically inactive. But some recent studies have shown that the Lys49 PLA2 is able to bind to the KDR (receptor of the VEGF165 growth factor)and this corresponds to his myotoxic activity. 


Venoms of snake contain a lot of  basic phospholipidases A2 , that play roles in the pathogenesis of myonecrosis. But there are also a subgroup of catalytically inactive variants or PLA2 homologue in which the conserved Asp at position 49 is replaced by <scene name='Sandbox136/Lys_49/1'>Lys</scene>. This substitution take place on the binding site of Ca2+  an essential cofactor.
Vascular endothelial growth factor (VEGF165) and its receptor Kinase insert domain containing receptor (KDR) are used in mechanisms of regulations of blood vessel formations. Experiments have revealed that the venom extracted from Agkistrodon piscivorus  contains a KDR binding protein.It has been shown that this KDRb-p was in fact a Lys49 PLA2.Lys49 is able to bind to the extracellular domain of  KDR receptors with a sub-nanomolar affinity. Recently studies revealed the fact that the region of the protein involved in the fixation on KDR was located in the C-terminal region. C- terminal region differ from the rest of the protein in his amino acid sequence,  indeed some amino-acids are positive (K,R) and seem to play a role in the recognition and fixation on KDR.
 
Vascular endothelial growth factor (VEGF165) and its receptor Kinase insert domain containing receptor (KDR) are use in mechanisms of regulations of blood vessel formations. Experiments have revealed that the venom extract from Agkistrodon piscivorus  contained a KDR binding protein., it has been show that this KDRb-p was in fact a Lys49 PLA2. . Lys49 is able to bind to the extracellular domain of  KDR receptors sub-nanomolar affinity. It had been show recently that the region of the protein involved in the fixation on KDR was located in the C-terminal region. C- terminal region differ from the rest of the protein in his amino acid sequence,  indeed amino acids are essentially positive (K,R) and aromatic (F,Y,...) and seem to play a role in the recognition and fixation on KDR
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