Palmitoyl protein thioesterase: Difference between revisions
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{{BAMBED | |||
|DATE=May 3, 2014 | |||
|OLDID=1923505 | |||
|BAMBEDDOI=10.1002/bmb.20840 | |||
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<StructureSection load='3GRO' size='450' side='right' caption='Human Palmitoyl-protein thioesterase 1 (PPT-1) homodimer (PDB: [[3gro]])' scene='43/436866/Overall-3-rainbow/1' > | <StructureSection load='3GRO' size='450' side='right' caption='Human Palmitoyl-protein thioesterase 1 (PPT-1) homodimer (PDB: [[3gro]])' scene='43/436866/Overall-3-rainbow/1' > | ||
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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== | ||
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===Mutations leading to Juvenile Neuronal Ceroid Lipofuscinosis=== | ===Mutations leading to Juvenile Neuronal Ceroid Lipofuscinosis=== | ||
JNCL is caused by a mutation in the CLN3 gene which codes for a lysosomal membrane protein of unknown function <ref name="Ryan-3">PMID:9151311</ref>. Unlike the mutations that cause INCL and LINCL, mutations that lead to JNCL are located away from the active site and are seen to cause less damage to the overall structure of PPT-1. Some of the mutations in JNCL have been noted as retaining a low level of PPT-1 activity as the catalytic site is left fairly unperturbed. Mutations associated with JNCl are found in two locations, Thr75Pro with Asp79Gly and <scene name='58/580837/Juvenile_mutation/4'>Tyr247His with Gly250Val</scene>. These mutations occur in conjugate with its other pair and are predicted to disturb the geometry of helix α1, increasing the flexibility of the region, and alter the antiparallel βsheet motif in sheets βa and βb compared to the <scene name='58/580837/Tyrosine_normal/2'>normal Tyr-247 and Gly-250</scene>. | JNCL is caused by a mutation in the CLN3 gene which codes for a lysosomal membrane protein of unknown function <ref name="Ryan-3">PMID:9151311</ref>. Unlike the mutations that cause INCL and LINCL, mutations that lead to JNCL are located away from the active site and are seen to cause less damage to the overall structure of PPT-1. Some of the mutations in JNCL have been noted as retaining a low level of PPT-1 activity as the catalytic site is left fairly unperturbed. Mutations associated with JNCl are found in two locations, Thr75Pro with Asp79Gly and <scene name='58/580837/Juvenile_mutation/4'>Tyr247His with Gly250Val</scene>. These mutations occur in conjugate with its other pair and are predicted to disturb the geometry of helix α1, increasing the flexibility of the region, and alter the antiparallel βsheet motif in sheets βa and βb compared to the <scene name='58/580837/Tyrosine_normal/2'>normal Tyr-247 and Gly-250</scene>. | ||
=3D structures of palmitoyl protein thioesterase= | |||
[[Thioesterase]] | |||
</StructureSection> | </StructureSection> | ||
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Audrey Wright | Audrey Wright | ||
[[Category:Featured in BAMBED]] | |||