Palmitoyl protein thioesterase: Difference between revisions
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'''<scene name='43/436866/Overall-3-rainbow/1'>Palmitoyl-protein thioesterase 1 (PPT-1)</scene>''' is a small glycoprotein [[hydrolase]] found in the lysosome that breaks the thioester bond between cysteine [[amino acids]] and <scene name='43/436866/Palmitic_acid_self/2'>palmitic acid</scene><ref name="newest">PMID:24083319</ref>. PPT-1 is a homodimer that is composed primarily of alpha helices and beta sheets with a <scene name='58/580839/Narrow_binding_groove/1'>hydrophobic groove</scene> that allows the [http://en.wikipedia.org/wiki/Palmitic_acid palmitic acid] to bind, exposing the thioester bond to the catalytic triad. PPT-1 was first found as an enzyme that removed palmitate from [[GTPase HRas]] and now has many additional cellular substrates <ref name="mutations">PMID:10781062</ref>. When PPT-1 is not functioning properly, lipid modified proteins can build up in the cells, causing lysosomal storage diseases and aiding in tumor formation <ref name="INCL">PMID:19302939</ref>. | '''<scene name='43/436866/Overall-3-rainbow/1'>Palmitoyl-protein thioesterase 1 (PPT-1)</scene>''' is a small glycoprotein [[hydrolase]] found in the lysosome that breaks the thioester bond between cysteine [[amino acids]] and <scene name='43/436866/Palmitic_acid_self/2'>palmitic acid</scene><ref name="newest">PMID:24083319</ref>. PPT-1 is a homodimer that is composed primarily of alpha helices and beta sheets with a <scene name='58/580839/Narrow_binding_groove/1'>hydrophobic groove</scene> that allows the [http://en.wikipedia.org/wiki/Palmitic_acid palmitic acid] to bind, exposing the thioester bond to the catalytic triad. PPT-1 was first found as an enzyme that removed palmitate from [[GTPase HRas]] and now has many additional cellular substrates <ref name="mutations">PMID:10781062</ref>. When PPT-1 is not functioning properly, lipid modified proteins can build up in the cells, causing lysosomal storage diseases and aiding in tumor formation <ref name="INCL">PMID:19302939</ref>. | ||
[[Image:Protopedia_surface_w_acid.png |300px|left|thumb|Figure 1: Surface view of PPT-1 (green) showing the hydrophobic groove and palmitate (blue with red oxygen)]] | [[Image:Protopedia_surface_w_acid.png |300px|left|thumb|Figure 1: Surface view of PPT-1 (green) showing the hydrophobic groove and palmitate (blue with red oxygen)]] | ||
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== Structure == | == Structure == | ||
The secondary structure of PPT1 contains several α-helices and few β-sheets (Figure 1). PPT1 includes residues 28-306, after the 27-residue signal peptide has been removed <ref name="RSCB">PMID:10781062</ref>. An insertion is found between β6 and β7, residues 140-223, and that forms a <scene name='57/573128/9/1'>second domain</scene>, shown in blue, that is compromised almost entirely of the fatty acid binding site. This second domain region contains six helices, α2-α7<ref name="RSCB"/>. | The secondary structure of PPT1 contains several α-helices and few β-sheets (Figure 1). PPT1 includes residues 28-306, after the 27-residue signal peptide has been removed <ref name="RSCB">PMID:10781062</ref>. An insertion is found between β6 and β7, residues 140-223, and that forms a <scene name='57/573128/9/1'>second domain</scene>, shown in blue, that is compromised almost entirely of the fatty acid binding site. This second domain region contains six helices, α2-α7<ref name="RSCB"/>. | ||
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===Hydrophobic Groove === | ===Hydrophobic Groove === | ||
The <scene name='57/573128/3/1'>hydrophobic binding groove</scene> is located in the second domain of PPT1 | The <scene name='57/573128/3/1'>hydrophobic binding groove</scene> where palmitate binds is located in the second domain of PPT1. (<scene name='48/489312/Binding_groove/4'>This alternate view</scene> shows the protein-ligand complex in the same orientation as Figure 1 above for better comparison). The fact that palmitate has to <scene name='57/573128/6/1'>bend</scene> to fit into the binding pocket suggests that this pocket is designed to bind an unsaturated fatty acid, with a possible cis-double bond between C4 and C5 (Figure 1)<ref name="RSCB"/>. The top portion of the groove is formed by the residues from α2 to α3. The acid binds in a [https://en.wikipedia.org/wiki/Gauche_effect gauche conformation] creating a <scene name='58/580839/Kink_in_acid/1'>kink </scene> in the acid chain. This bending suggests that PPT-1 was originally designed to react with an unsaturated fatty acid with cis-double bonds. Several residues that are present near the active site create the rest of the groove, including <scene name='57/573128/10/1'>Ile235, Val236, Gln116, Gly40, and Met41</scene><ref name="RSCB"/>. | ||
==Catalytic Triad== | ==Catalytic Triad== | ||