Caspase-3 Regulatory Mechanisms: Difference between revisions

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Scott Eron, Banyuhay P. Serrano, Yunlong Zhao, Jaime Prilusky, Michal Harel, Alexander Berchansky

Revision as of 03:42, 13 December 2012 view source Banyuhay P. Serrano (talk \| contribs) 48 edits No edit summary ← Older edit		Revision as of 03:48, 13 December 2012 view source Scott Eron (talk \| contribs) 114 edits →‎Caspase-3 Loop Bundle and Active Site Newer edit →
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	The active site of caspase-3 utilizes a cysteine-histidine dyad, which has an exquisite specificity for cleaving after aspartate residues. Therefore, caspase-3, by definition, will have an aspartate in the <scene name='Caspase-3_Regulatory_Mechanisms/P1/2'>P1</scene> pocket. Uncleavable peptide substrates are often used in crystallography to bind to the active site. This will orient the delicate but deadly active site loops in order to facilitate the visualization of the chemistry of cleavage. The nucleophilic Cysteine 163 will work in concert with the second active site residue, Histidine 121, to attack the substrate. This reaction will ultimately cleave the peptide bond following the aspartate.		The active site of caspase-3 utilizes a cysteine-histidine dyad, which has an exquisite specificity for cleaving after aspartate residues. Therefore, caspase-3, by definition, will have an aspartate in the <scene name='Caspase-3_Regulatory_Mechanisms/P1/2'>P1</scene> pocket. Uncleavable peptide substrates are often used in crystallography to bind to the active site. This will orient the delicate but deadly active site loops in order to facilitate the visualization of the chemistry of cleavage. The nucleophilic Cysteine 163 will work in concert with the second active site residue, Histidine 121, to attack the substrate. This reaction will ultimately cleave the peptide bond following the aspartate.

	In order to be active and cleave ~~the~~ specific apoptotic targets, Caspase-3 must be able to first bind substrate. There are several essential interactions responsible for securing the substrate before cleavage. The binding pocket at <scene name='Caspase-3_Regulatory_Mechanisms/P2/2'>P2</scene> is a hydrophobic patch made up of Y204, W206, and F250 (dark blue residues). This creates a hydrophobic pocket for the P2 residue (in this ~~casse~~, valine). At <scene name='Caspase-3_Regulatory_Mechanisms/P4/2'>P4</scene> there are contacts that contribute to the specificity of caspase-3. Asparagine 208 hydrogen bonds with an aspartate at P4 along with the backbone nitrogen of F250, creating a preference for a carboxylic acid at the P4 site.		In order to be active and cleave specific apoptotic targets, Caspase-3 must be able to first bind substrate. There are several essential interactions responsible for securing the substrate before cleavage. The binding pocket at <scene name='Caspase-3_Regulatory_Mechanisms/P2/2'>P2</scene> is a hydrophobic patch made up of Y204, W206, and F250 (dark blue residues). This creates a hydrophobic pocket for the P2 residue (in this case, valine), helping it stick to the protein. At <scene name='Caspase-3_Regulatory_Mechanisms/P4/2'>P4</scene> there are contacts that contribute to the specificity of caspase-3. Asparagine 208 hydrogen bonds with an aspartate at P4 along with the backbone nitrogen of F250, creating a preference for a carboxylic acid at the P4 site.