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Biomolecules 2014, 4(2), 510-526; doi:10.3390/biom4020510
Article

Prion Fragment Peptides Are Digested with Membrane Type Matrix Metalloproteinases and Acquire Enzyme Resistance through Cu2+-Binding

1,2
,
1
 and
1,*
1 Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan 2 Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 180-8639, Japan
* Author to whom correspondence should be addressed.
Received: 31 January 2014 / Revised: 2 April 2014 / Accepted: 11 April 2014 / Published: 8 May 2014
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Abstract

Prions are the cause of neurodegenerative disease in humans and other mammals. The structural conversion of the prion protein (PrP) from a normal cellular protein (PrPC) to a protease-resistant isoform (PrPSc) is thought to relate to Cu2+ binding to histidine residues. In this study, we focused on the membrane-type matrix metalloproteinases (MT-MMPs) such as MT1-MMP and MT3-MMP, which are expressed in the brain as PrPC-degrading proteases. We synthesized 21 prion fragment peptides. Each purified peptide was individually incubated with recombinant MT1-MMP or MT3-MMP in the presence or absence of Cu2+ and the cleavage sites determined by LC-ESI-MS analysis. Recombinant MMP-7 and human serum (HS) were also tested as control. hPrP61-90, from the octapeptide-repeat region, was cleaved by HS but not by the MMPs tested here. On the other hand, hPrP92-168 from the central region was cleaved by MT1-MMP and MT3-MMP at various sites. These cleavages were inhibited by treatment with Cu2+. The C-terminal peptides had higher resistance than the central region. The data obtained from this study suggest that MT-MMPs expressed in the brain might possess PrPC-degrading activity.
Keywords: prion protein; fragment peptide; MT1-MMP; MT3-MMP; MMP-7; Cu2+; degradation prion protein; fragment peptide; MT1-MMP; MT3-MMP; MMP-7; Cu2+; degradation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Kojima, A.; Konishi, M.; Akizawa, T. Prion Fragment Peptides Are Digested with Membrane Type Matrix Metalloproteinases and Acquire Enzyme Resistance through Cu2+-Binding. Biomolecules 2014, 4, 510-526.

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