User:Emily Leiderman/Sandbox 1
From Proteopedia
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== Introduction == | == Introduction == | ||
The reversible [https://en.wikipedia.org/wiki/Acetylation acetylation] | The reversible [https://en.wikipedia.org/wiki/Acetylation acetylation] | ||
| - | of lysine residues of [https://en.wikipedia.org/wiki/Histone histones] has been proven to play an important role in the regulation of heterochromatin (inactive) and euchromatin (active) <ref>PMID:7559580</ref>. The role of the protein Histone Acetyltransferase is to transfer an acetyl group from <scene name='81/811098/Acetyl_coa/5'>Acetyl-CoA</scene> to a lysine group found on a histone <ref>PMID:26745824 </ref>. This results in an increase in gene activity as the addition of acetyl groups to histones results in the formation of euchromatin <ref>PMID:9727486 </ref>. In this study we analyzed the structure and function of the HAT1 gene that’s derived from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] <ref>PMID:28666361 </ref>. Analysis of the various binding sites and interaction mechanisms involved in the acetylation process in addition to the initial [https://en.wikipedia.org/wiki/Acetyl-CoA Acetyl CoA] binding mechanism. | + | of lysine residues of [https://en.wikipedia.org/wiki/Histone histones] has been proven to play an important role in the regulation of heterochromatin (inactive) and euchromatin (active) <ref name=Kleff>PMID:7559580</ref>. The role of the protein Histone Acetyltransferase is to transfer an acetyl group from <scene name='81/811098/Acetyl_coa/5'>Acetyl-CoA</scene> to a lysine group found on a histone <ref name=Des>PMID:26745824 </ref>. This results in an increase in gene activity as the addition of acetyl groups to histones results in the formation of euchromatin <ref name=Dut>PMID:9727486 </ref>. In this study we analyzed the structure and function of the HAT1 gene that’s derived from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] <ref name=Aug>PMID:28666361 </ref>. Analysis of the various binding sites and interaction mechanisms involved in the acetylation process in addition to the initial [https://en.wikipedia.org/wiki/Acetyl-CoA Acetyl CoA] binding mechanism. |
== Structure == | == Structure == | ||
The structure of HATs consist of a | The structure of HATs consist of a | ||
| - | <scene name='81/811098/Motif/1'>motif</scene> with at least 3 stranded antiparallel [https://en.wikipedia.org/wiki/Beta_sheet β-sheets] and one [https://en.wikipedia.org/wiki/Alpha_helix α-helix] spanning the length of the sheet. Specifically, Hat1 has an elongated and curved structure that is comprised of 320 residues. The elongated shape of Hat1 allows for the formation of a concave surface where Acetyl CoA binds to the protein. | + | <scene name='81/811098/Motif/1'>motif</scene> with at least 3 stranded antiparallel [https://en.wikipedia.org/wiki/Beta_sheet β-sheets] and one [https://en.wikipedia.org/wiki/Alpha_helix α-helix] spanning the length of the sheet <ref>PMID:7559580. Specifically, Hat1 has an elongated and curved structure that is comprised of 320 residues. The elongated shape of Hat1 allows for the formation of a concave surface where Acetyl CoA binds to the protein. |
=== Domains === | === Domains === | ||
It is composed of a mixture of helices and sheets that form two domains. The domains are connected via an extended loop region that together make up the quaternary structure of the protein. The <scene name='81/811098/N-terminal_domain/8'>N-terminal domain</scene> stretches from residues 2-111 and the | It is composed of a mixture of helices and sheets that form two domains. The domains are connected via an extended loop region that together make up the quaternary structure of the protein. The <scene name='81/811098/N-terminal_domain/8'>N-terminal domain</scene> stretches from residues 2-111 and the | ||
| - | <scene name='81/811098/C-terminal_domain/3'>C-terminal domain</scene> extends from residues 122-320. Residues 112–121 are what are thought to construct the extended loop that connects the two domains. Additionally, the C-terminal domain contains the active site. | + | <scene name='81/811098/C-terminal_domain/3'>C-terminal domain</scene> extends from residues 122-320 <ref>PMID:9727486 </ref>. Residues 112–121 are what are thought to construct the extended loop that connects the two domains. Additionally, the C-terminal domain contains the active site <ref>PMID:9727486 </ref>. |
=== Active Site === | === Active Site === | ||
| - | The concave groove mentioned above is where Acetyl CoA binds and is known to be the [https://en.wikipedia.org/wiki/Active_site active site] of the enzyme. The groove contains approximately 1100 Å of accessible surface area. Because Acetyl CoA exhibits a bent shape it is thought that the ligand is able to wrap itself around the protein upon binding. Functional studies state that a [https://en.wikipedia.org/wiki/Conformational_change conformational change] is likely after Acetyl CoA is bound; this conformational change results in the formation of a binding cleft for the target lysine residue to enter the backside of the active site to be Acetylated. The binding of the target histone does not result in any conformational change. The Lys-12 side chain is able to approach the carbonyl group from the backside of the active site adjacent to the gating region. Near 60% of the Acetyl CoA molecule is found buried in a highly non-polar region of the protein surface called the hydrophobic pocket. | + | The concave groove mentioned above is where Acetyl CoA binds and is known to be the [https://en.wikipedia.org/wiki/Active_site active site] of the enzyme. The groove contains approximately 1100 Å of accessible surface area <ref>PMID:9727486 </ref>. Because Acetyl CoA exhibits a bent shape it is thought that the ligand is able to wrap itself around the protein upon binding. Functional studies state that a [https://en.wikipedia.org/wiki/Conformational_change conformational change] is likely after Acetyl CoA is bound; this conformational change results in the formation of a binding cleft for the target lysine residue to enter the backside of the active site to be Acetylated <ref>PMID:9727486 </ref>. The binding of the target histone does not result in any conformational change. The Lys-12 side chain is able to approach the carbonyl group from the backside of the active site adjacent to the gating region. Near 60% of the Acetyl CoA molecule is found buried in a highly non-polar region of the protein surface called the hydrophobic pocket. |
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The active site consists of the Acetyl CoA ligand bound to the enzyme in a groove on the surface of the protein. The [https://en.wikipedia.org/wiki/Ligand ligand] is held in place by several bonds to protein residues that result in the formation of a <scene name='81/811098/Hydrophobic_pocket/1'>hydrophobic pocket</scene>. The hydrophobic pocket consists of the interacting side chains from residues | The active site consists of the Acetyl CoA ligand bound to the enzyme in a groove on the surface of the protein. The [https://en.wikipedia.org/wiki/Ligand ligand] is held in place by several bonds to protein residues that result in the formation of a <scene name='81/811098/Hydrophobic_pocket/1'>hydrophobic pocket</scene>. The hydrophobic pocket consists of the interacting side chains from residues | ||
<scene name='81/811098/Ile-217/3'>Ile-217</scene>, <scene name='81/811098/Pro-257/2'>Pro-257</scene>, | <scene name='81/811098/Ile-217/3'>Ile-217</scene>, <scene name='81/811098/Pro-257/2'>Pro-257</scene>, | ||
| - | <scene name='81/811098/Phe-261/2'>Phe-261</scene>, in addition to further bonds resulting from residues 217-220 and 255-256 | + | <scene name='81/811098/Phe-261/2'>Phe-261</scene>, in addition to further bonds resulting from residues 217-220 and 255-256 <ref>PMID:9727486 </ref>. The amide of main-chain |
<scene name='81/811098/Phe-220/2'>Phe-220</scene> hydrogen bonds to the carbonyl oxygen of the Acetyl group in the binding pocket. The main-chain amide of | <scene name='81/811098/Phe-220/2'>Phe-220</scene> hydrogen bonds to the carbonyl oxygen of the Acetyl group in the binding pocket. The main-chain amide of | ||
| - | <scene name='81/811098/Asn-258/2'>Asn-258</scene> also donates a hydrogen bond from its side chain to oxygen PO5 of the pantothenic acid group | + | <scene name='81/811098/Asn-258/2'>Asn-258</scene> also donates a hydrogen bond from its side chain to oxygen PO5 of the pantothenic acid group <ref>PMID:9727486 </ref>. The binding within the hydrophobic pocket is further supplemented through the creation of a protein gate that establishes a bridge over the concave surface that serves to keep Acetyl CoA in place while the enzyme interacts with the histone. |
Revision as of 03:43, 9 April 2019
Histone Acetyltransferase HAT1
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