User:Luke Edward Severinac/Sandbox 1
From Proteopedia
(Difference between revisions)
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In addition to a self-cleavage mechanism, Caspase-6 <scene name='75/752344/Caspase-6_zymogen_yeahboi/1'>zymogen</scene> can be activated getting cleaved by Caspase-3, as well as other enzymes. The mechanism of activation by clevage is highly conserved across the caspase family; Self-processing is uniquely recognized as the primary mechanism for Caspase-6 activation, where clevage must occur at <scene name='75/752344/Caspase-6_cleavage_sites_real/1'>three sites</scene> for complete activation, specifically the <scene name='75/752344/Caspase-6_prodomain/1'>pro-domain</scene> and the <scene name='75/752344/Caspase-6_intersubunit_linker/1'>intersubunit linker</scene> must be removed. These cleavages are both sequence specific and ordered, starting with cleavage of the pro-domain at <scene name='75/752344/Caspase-6_prodomain_cleavage/1'>residue 30</scene>. Then removal of the intersubunit linker occurs through cleavage at two sites, <scene name='75/752344/Caspase-6_176-179_cleavageyis/1'>DVVD179 and TEVD193</scene>. It has been proposed that this sequence of cleavage is due to the pro-domain being more readily available to enter the active site, whose presence inhibits Caspase-6's ability to cleave the intersubunit loop and self-activate; The prodomain acts as a “suicide protector”, preventing the TEVD193 cleavage site from the active site[3]. After both cleavages occur, <scene name='75/752344/Active_caspase_6_dimer/1'>active caspase-6</scene> remains in solution as a dimer. | In addition to a self-cleavage mechanism, Caspase-6 <scene name='75/752344/Caspase-6_zymogen_yeahboi/1'>zymogen</scene> can be activated getting cleaved by Caspase-3, as well as other enzymes. The mechanism of activation by clevage is highly conserved across the caspase family; Self-processing is uniquely recognized as the primary mechanism for Caspase-6 activation, where clevage must occur at <scene name='75/752344/Caspase-6_cleavage_sites_real/1'>three sites</scene> for complete activation, specifically the <scene name='75/752344/Caspase-6_prodomain/1'>pro-domain</scene> and the <scene name='75/752344/Caspase-6_intersubunit_linker/1'>intersubunit linker</scene> must be removed. These cleavages are both sequence specific and ordered, starting with cleavage of the pro-domain at <scene name='75/752344/Caspase-6_prodomain_cleavage/1'>residue 30</scene>. Then removal of the intersubunit linker occurs through cleavage at two sites, <scene name='75/752344/Caspase-6_176-179_cleavageyis/1'>DVVD179 and TEVD193</scene>. It has been proposed that this sequence of cleavage is due to the pro-domain being more readily available to enter the active site, whose presence inhibits Caspase-6's ability to cleave the intersubunit loop and self-activate; The prodomain acts as a “suicide protector”, preventing the TEVD193 cleavage site from the active site[3]. After both cleavages occur, <scene name='75/752344/Active_caspase_6_dimer/1'>active caspase-6</scene> remains in solution as a dimer. | ||
- | ==Active State== | + | =='''Active State'''== |
[[Image:Binding grove active caspase 6.png|100 px|right|thumb|Substrate binding groove in Caspase-6. Blue - catalytic residues | [[Image:Binding grove active caspase 6.png|100 px|right|thumb|Substrate binding groove in Caspase-6. Blue - catalytic residues | ||
yellow - ligand | yellow - ligand | ||
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[[Image:Cystine Aspartase.png|600 px|active site mechanism]] | [[Image:Cystine Aspartase.png|600 px|active site mechanism]] | ||
- | ==Zinc Inhibition== | + | =='''Zinc Inhibition'''== |
Caspase-6 can also assume an inactive state, which exists as a <scene name='75/752344/Casp_6_inactive_dimer/1'>dimer</scene> in its biological unit. For each <scene name='75/752344/Casp_6_inactive_monomer/1'>monomer</scene>, Caspase-6 function is primarily inhibited by the binding of a <scene name='75/752344/Casp_6_inactive_monomer_zinc/1'>zinc</scene> ion, which binds to an <scene name='75/752344/Casp_6_alosteric_site/1'>allosteric site</scene> instead of the <scene name='75/752344/Casp_6_alostericactive_site/1'>active site</scene>. This allosteric site is located on the opposite side of the protein relative to the active site. The zinc ion is bound to <scene name='75/752344/Caspase6_alloster_resid/1'>three residues</scene>, Lys-36, Glu-244, and His-287. Once the ion is bound to the protein, it is then stabilized by a <scene name='75/752344/Caspase6_alloster_h20/1'>water molecule</scene> found in the cytoplasm. The binding of zinc at the exosite is suggested to cause a conformational change in the protein from an <scene name='75/752344/Catalytic_triad_real_monomer/1'>active state</scene> to an <scene name='75/752344/Casp_6_inactive_cat_triad/1'>inactive state</scene> that misaligns catalytic residues and inhibits activity of the enzyme. It has been proposed that helices of the active dimer must rotate or move in some other way to provide these ideal interactions with zinc. This subtle shift is most likely the cause for allosteric inhibition. As the helices move to bind zinc, the amino acids of the active site become misaligned. The altered positions of the amino acids no longer provide ideal interactions for incoming substrates. After zinc binds, substrates may still enter the active site, but no catalytic activity will occur. | Caspase-6 can also assume an inactive state, which exists as a <scene name='75/752344/Casp_6_inactive_dimer/1'>dimer</scene> in its biological unit. For each <scene name='75/752344/Casp_6_inactive_monomer/1'>monomer</scene>, Caspase-6 function is primarily inhibited by the binding of a <scene name='75/752344/Casp_6_inactive_monomer_zinc/1'>zinc</scene> ion, which binds to an <scene name='75/752344/Casp_6_alosteric_site/1'>allosteric site</scene> instead of the <scene name='75/752344/Casp_6_alostericactive_site/1'>active site</scene>. This allosteric site is located on the opposite side of the protein relative to the active site. The zinc ion is bound to <scene name='75/752344/Caspase6_alloster_resid/1'>three residues</scene>, Lys-36, Glu-244, and His-287. Once the ion is bound to the protein, it is then stabilized by a <scene name='75/752344/Caspase6_alloster_h20/1'>water molecule</scene> found in the cytoplasm. The binding of zinc at the exosite is suggested to cause a conformational change in the protein from an <scene name='75/752344/Catalytic_triad_real_monomer/1'>active state</scene> to an <scene name='75/752344/Casp_6_inactive_cat_triad/1'>inactive state</scene> that misaligns catalytic residues and inhibits activity of the enzyme. It has been proposed that helices of the active dimer must rotate or move in some other way to provide these ideal interactions with zinc. This subtle shift is most likely the cause for allosteric inhibition. As the helices move to bind zinc, the amino acids of the active site become misaligned. The altered positions of the amino acids no longer provide ideal interactions for incoming substrates. After zinc binds, substrates may still enter the active site, but no catalytic activity will occur. | ||
===Phosphorylation=== | ===Phosphorylation=== |
Revision as of 04:52, 21 April 2017
Caspase-6 in Homo sapiens
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