A new function of human HtrA2 as an amyloid-beta oligomerization inhibitor.
Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the intermembrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in Alzheimer's disease (AD), which is characterized by the presence of aggregates of the amyloid-beta peptide 1-42 (Abeta1-42). In this study, we analyzed the ability of HtrA2 to delay the aggregation of the model substrate citrate synthase (CS) and of the toxic Abeta1-42 peptide. We found that HtrA2 had a moderate ability to delay the aggregation of CS in vitro, and this activity was significantly enhanced when the PDZ domain was removed suggesting an inhibitory role for this domain on the activity. Additionally, using electron microscopy and nuclear magnetic resonance analyses, we observed that HtrA2 significantly delayed the aggregation of the Abeta1-42 peptide. Interestingly, the protease activity of HtrA2 and its PDZ domain were not essential for the delay of Abeta1-42 peptide aggregation. These results indicate that besides its protease activity, HtrA2 also performs a chaperone function and suggest a role for HtrA2 in the metabolism of intracellular Abeta and in AD.
Kooistra
Joel
J
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Milojevic
Julijana
J
Melacini
Giuseppe
G
Ortega
Joaquin
J
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D002950:Citrate (si)-Synthase / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D016297:Mutagenesis, Site-Directed / Q000379:methods; D054731:PDZ Domains / Q000235:genetics / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding / Q000502:physiology; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000502:physiology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002950:Citrate (si)-Synthase; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2