Sandbox Reserved 191: Difference between revisions

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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA, R. Jeremy Johnson, Andrew Bartels, Ryan Mughmaw

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 ====Arg122Trp====
-The most common mutation in INCL that occurs in PPT-1 is a single missense mutation of  Arg122Trp. <scene name='58/580837/Arginine_fine/2'>Arg-122</scene> is located immediately after the nucleophilic elbow of PPT-1.  The sidechain of Arg-122 has a main function to control the spacing between the αC and  α6 helices in this region. This is done by Arg-122 having <scene name='58/580837/Arginine_fine/3'>Three Hydrogen Bonds</scene> with three adjacent amino acids:  Ile-205, Asn-206, and Gln-205. “<scene name='58/580837/Trp122_mutation/22'>Mutation of Arg-122 to Trp</scene>  means not only a loss of those three hydrogen bonds but also a steric and polarity mismatch with the surrounding residues” <ref name="mutations" />. These <scene name='58/580837/Trp122_mutation/23'>Steric Clashes</scene> will cause a misfolding of the enzyme’s core and cause it to be trapped in the endoplasmic reticulum which results in no detectable PPT-1 activity.
+The most common mutation in INCL that occurs in PPT-1 is a single missense mutation of  Arg122Trp. <scene name='58/580837/Arginine_fine/2'>Arg-122</scene> is located immediately after the nucleophilic elbow of PPT-1.  The sidechain of Arg-122 has a main function to control the spacing between the αC and  α6 helices in this region. This is done by Arg-122 having <scene name='58/580837/Arginine_fine/3'>three hydrogen bonds</scene> with three adjacent amino acids:  Ile-205, Asn-206, and Gln-205. <scene name='58/580837/Trp122_mutation/22'>Mutation of Arg-122 to Trp</scene>  means not only a loss of those three hydrogen bonds but also a steric and polarity mismatch with the surrounding residues <ref name="mutations" />. These <scene name='58/580837/Trp122_mutation/23'>Steric Clashes</scene> will cause a misfolding of the enzyme’s core and cause it to be trapped in the endoplasmic reticulum, which results in no detectable PPT-1 activity.
 ==Late-Infantile and Juvenile Neuronal Ceroid Lipofuscinosis==
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 ===Mutations leading to Late-Infantile Neuronal Ceroid Lipofuscinosis===
-LINCl is caused by a mutation in the CLN2 gene which “codes for a lysosomal pepstatin-insensitive acid protease that is deficient in LINCL patients”<ref name="Ryan-2">PMID:9989590</ref> . Mutations that tend to lead to LINCL still disrupt the active site and binding pocket geometry but do not do it to the degree that is seen in INCL. One LINCL mutation is <scene name='58/580837/Multiple_mutations_mutating/4'>Gln177Glu</scene>. The <scene name='58/580837/Multiple_mutations/4'>Gln-177</scene> acts as a hydrogen bond donor to Ala-171 and Ala-183 and as a hydrogen bond acceptor from Ile-200. It is presumed that the mutation to Glu-177 would cause a conformation change of the helices in the area. Ala-171 and Ala-183 make hydrophobic contact with the palmitate, and so the altered conformation associated with those two amino acids would decrease binding affinity of the palmitate, decreasing the catalytic activity but not to the extent of the mutations seen in INCL.
+LINCl is caused by a mutation in the CLN2 gene which “codes for a lysosomal pepstatin-insensitive acid protease that is deficient in LINCL patients”<ref name="Ryan-2">PMID:9989590</ref> . Mutations that tend to lead to LINCL still disrupt the active site and binding pocket geometry, but not to the degree that is seen in INCL. One LINCL mutation is <scene name='58/580837/Multiple_mutations_mutating/4'>Gln177Glu</scene>.  <scene name='58/580837/Multiple_mutations/4'>Gln-177</scene> acts as a hydrogen bond donor to Ala-171 and Ala-183 and as a hydrogen bond acceptor from Ile-200. The mutation of Gln-177 likely causes a conformation change of the helices in the area. Ala-171 and Ala-183 make hydrophobic contact with the palmitate, and so the altered conformation associated with those two amino acids would decrease binding affinity of the palmitate, decreasing, but not killing the catalytic activity of PPT-1.
 ===Mutations leading to Juvinile 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/3'>Tyr247His with Gly250Val</scene>. These mutations are predicted to disturb the geometry of α1, increase the flexibility of the region, and alter the antiparallel βsheet motif in βa and βb compared to the <scene name='58/580837/Tyrosine_normal/1'>Normal Tyr-247 & 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/3'>Tyr247His with Gly250Val</scene>. These mutations 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/1'>Normal Tyr-247 & Gly-250</scene>.