Sandbox Reserved 191: Difference between revisions
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[[Image:Thr-_mut.png|200px|left|thumb|Figure 4: Common Mutation associated with JNCL and LINCL involve mutations far away from the active Ser-115. ]] | [[Image:Thr-_mut.png|200px|left|thumb|Figure 4: Common Mutation associated with JNCL and LINCL involve mutations far away from the active Ser-115. ]] | ||
===Mutations | ===Mutations leading to Infantile Neuronal Ceroid Lipofuscinosis=== | ||
Various mutations have been found in INCL patients<ref name="Ryan-1">PMID:10191107</ref> . Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT-1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow. The nucleophilic elbow is responsible for proper location and orientation of the Ser-115. Catalytic ability would be greatly reduced if the original position of Ser-115 was altered because it must be properly orientated to be activated by His-289 in order to attack the substrate. An example of a JNCL mutation such as <scene name='58/580837/Methionine/6'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/3'>Glu184Lys</scene> gives a good depiction of how the increase in size in the mutated amino acids and positive charge on lysine mutation would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val-181 & Glu-184</scene> <scene name='58/580837/Arginine_fine/4'>Normal Arg-122</scene> which is described in more detail below. | Various mutations have been found in INCL patients<ref name="Ryan-1">PMID:10191107</ref> . Most of these mutations are caused by nonsense or missense mutations within close proximity to the catalytic triad. These mutations lead to an inactive PPT-1 enzyme as they are predicted to create unfavorable steric, polar, and electrostatic interactions that could disturb the nucleophilic elbow. The nucleophilic elbow is responsible for proper location and orientation of the Ser-115. Catalytic ability would be greatly reduced if the original position of Ser-115 was altered because it must be properly orientated to be activated by His-289 in order to attack the substrate. An example of a JNCL mutation such as <scene name='58/580837/Methionine/6'>Val181Met</scene> and <scene name='58/580837/Lysine_mutation/3'>Glu184Lys</scene> gives a good depiction of how the increase in size in the mutated amino acids and positive charge on lysine mutation would create steric and polar clashes with the adjacent helices of the binding pocket compared to the <scene name='58/580837/Val181glu184/2'>Normal Val-181 & Glu-184</scene> <scene name='58/580837/Arginine_fine/4'>Normal Arg-122</scene> which is described in more detail below. | ||