User:Sean Callahan/Sandbox 1: Difference between revisions
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LSD-1 will demethylate mono or di-methylated lysines. However it will not demethylate just any lysine. It will only demethylate lysine H3-K4. This factor can be regulated by the androgen receptor. The [http://proteopedia.org/wiki/index.php/Androgen_receptor#Function androgen receptor] is a protein that is involved in DNA transcription. When it interacts with LSD-1 it will no longer demethylate H3-K4, but will now demethylate H3-K9. This attribute allows LSD-1 to work on a wider range of residues<ref name="Stavropoulos">PMID: 16799558</ref>. | LSD-1 will demethylate mono or di-methylated lysines. However it will not demethylate just any lysine. It will only demethylate lysine H3-K4. This factor can be regulated by the androgen receptor. The [http://proteopedia.org/wiki/index.php/Androgen_receptor#Function androgen receptor] is a protein that is involved in DNA transcription. When it interacts with LSD-1 it will no longer demethylate H3-K4, but will now demethylate H3-K9. This attribute allows LSD-1 to work on a wider range of residues<ref name="Stavropoulos">PMID: 16799558</ref>. | ||
==Mechanism== | ===Mechanism=== | ||
The | The demethylation of lysine via LSD1 occurs through oxidation via a hydride transfer. Shown in Figure 2 the first step involves the <scene name='81/811710/Fad_highlight/1'>Flavin Adenine Dinucleotide cofactor</scene> initiating a hydride transfer from the one of the two methyl groups bound to the nitrogen at the lysine tail, via a N5 on the flavin group. An imine cation is then formed at the end of the lysine tail to compensate for the loss of hydride. The FAD co-factor is also negatively charged and lysine residue 661 provides stability by drawing that charge away. In the next step the imine is hydrolyzed and transitions to an hemiaminal. This then breaks down to formaldehyde and the product lysine. | ||
[[Image:LSD1Mech2.jpg|400px|right|thumb|Figure 2]] | |||
===Hydrophobic Pocket=== | ===Hydrophobic Pocket=== | ||
The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the | The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the | ||
FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. | FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/4'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/3'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. A structure complex of LSD1 with the a substrate lysine encased in has yet to be crystallized. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail. | ||
==Application== | ==Application== | ||
