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

Biomolecules

Aya Kojima¹  Motomi Konishi¹ 

[1] Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan; E-Mails:

关键词: prion protein;    fragment peptide;    MT1-MMP;    MT3-MMP;    MMP-7;    Cu²⁺;    degradation;   

DOI  :  10.3390/biom4020510

来源: mdpi

【 摘 要 】

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 (PrP^C) to a protease-resistant isoform (PrP^Sc) 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 PrP^C-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 PrP^C-degrading activity.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.