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In vitro depalmitoylation of neurospecific peptides: implication for infantile neuronal ceroid lipofuscinosis

Academic Article
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Overview

authors

  • Cho, S. G.
  • Dawson, Philip
  • Dawson, G.

publication date

  • January 2000

journal

  • Journal of Neuroscience Research  Journal

abstract

  • Palmitoyl protein thioesterase 1 (PPT1) removes palmitate from specific cysteine residues in peptides and proteins. We have previously shown that a palmitoylated myelin glycoprotein. Po octapeptide (IRYCWLRR) can be specifically depalmitoylated by PPT1 in vitro (Cho and Dawson [1998] J. Neurochem. 171 ;323-329). To characterize further the substrate specificity of PPT1, we prepared various palmitoylated oligopeptides, based on palmitoylated sequences from different proteins. A truncated tetrapeptide from Po (RY[palmitoyl]-CW) was as good a substrate as the octapeptide Po, with optimal activity at pH 4.0. In contrast, other peptide substrates showed marked differences. Thus, the deacylation of GAP-43 (MLCCMRR), rhodopsin (VTTLCCGKN), and Galpha subunit (MGCLGNSK) peptides was more efficient at neutral pH (7.4) than at acidic pH (4.0), with the greatest efficiency toward the Galpha peptide (five- to sixfold higher than other substrates). Infantile neuronal ceroid lipofuscinosis (INCL) is caused by PPT1 deficiency, and the absence of enzymatic activity was confirmed with GAP-43 peptide as well as the Po peptide. LA-N-5 human neuroblastoma cells overexpressing PPT1 showed increased depalmitoylation of all the peptide substrates, indicating that these peptides are deacylated by PPT1. An amide derivative of a palmitoylated K-Ras peptide (AcG-palmitoyl diamino propionate-VKIKK) acted as an enzyme pseudosubstrate and inhibited PPT1 enzyme activity in a dose-dependent manner. The peptide itself (AcGCVKIKK) did not affect PPT activity. In summary, PPT1 is able to hydrolyze a range of cysteinyl peptide sequences found in both neuron-specific and ubiquitous (e.g., Galpha) proteins. The inhibitor of PPT1 activity should facilitate the development of a model for INCL and help explain the neuronal death in this disease.

subject areas

  • Brain Neoplasms
  • Humans
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Infant, Newborn
  • Neuroblastoma
  • Neuronal Ceroid-Lipofuscinoses
  • Neuropeptides
  • Thiolester Hydrolases
  • Tumor Cells, Cultured
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Research

keywords

  • infantile neuronal ceroid lipofuscinosis
  • neuroblastoma cells
  • palmitoyl protein thioesterase 1
  • palmitoylation
  • peptide inhibitor
  • peptides
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Identity

International Standard Serial Number (ISSN)

  • 0360-4012

Digital Object Identifier (DOI)

  • 10.1002/(sici)1097-4547(20000101)59:1<32::aid-jnr5>3.0.co;2-a

PubMed ID

  • 10658183
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Additional Document Info

start page

  • 32

end page

  • 38

volume

  • 59

issue

  • 1

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