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Prion fragment peptides are digested with membrane type matrix metalloproteinases and acquire enzyme resistance

Aya Kojima1, Motomi Konishi2, Toshifumi Akizawa3

  • 1Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. ayak@ims.u-tokyo.ac.jp.

Biomolecules
|June 28, 2014
PubMed

Insights

Matrix metalloproteinases (MT-MMPs) in the brain may degrade the prion protein (PrPC). Copper ions (Cu2+) inhibited this degradation, suggesting a role in prion disease mechanisms.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Prions cause fatal neurodegenerative diseases by misfolding the prion protein (PrP).
  • Copper (Cu2+) binding to histidine residues is implicated in PrP structural conversion.
  • Membrane-type matrix metalloproteinases (MT-MMPs), including MT1-MMP and MT3-MMP, are brain proteases.

Purpose of the Study:

  • To investigate the potential of brain-expressed MT-MMPs to degrade the normal cellular prion protein (PrPC).
  • To determine the effect of Cu2+ on MT-MMP-mediated PrP cleavage.

Main Methods:

  • Synthesis and purification of 21 prion fragment peptides.
  • Incubation of peptides with recombinant MT1-MMP or MT3-MMP, with or without Cu2+.
  • Analysis of cleavage sites using Liquid Chromatography-Electrospray Ionization Mass Spectrometry (LC-ESI-MS).

Main Results:

  • MT1-MMP and MT3-MMP cleaved the central region of human PrP (hPrP92-168) at multiple sites.
  • Cu2+ inhibited the cleavage activity of MT-MMPs on PrP peptides.
  • Prion peptides from the C-terminal region exhibited greater resistance to cleavage than those from the central region.

Conclusions:

  • Brain-expressed MT-MMPs possess PrPC-degrading activity.
  • Cu2+ may play a regulatory role in MT-MMP-mediated PrPC degradation.
  • These findings offer insights into the biochemical pathways involved in prion pathogenesis.

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