cathepsin D
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Cathepsin D is peptidase belonging to the family of aspartic peptidases. Its mostly described function is intracellular catabolism in lysosomal compartments, other physiological effect include hormone and antigen processing. For almost two decades, there have been an increasing number of data describing additional roles imparted by cathepsin D and its pro-enzyme, resulting in cathepsin D being a specific biomarker of some diseases. These roles in pathological conditions, namely elevated levels in certain tumor tissues, seem to be connected to another, yet not fully understood functionality. However, despite numerous studies, the mechanisms of cathepsin D and its precursor's actions are still not completely understood. From results discussed in this article it might be concluded that cathepsin D in its zymogen status has additional function, which is rather dependent on a "ligand-like" function then on proteolytic activity.
- MeSH
- kathepsin D chemie metabolismus fyziologie MeSH
- lidé MeSH
- nádory patofyziologie MeSH
- prekurzory enzymů metabolismus fyziologie MeSH
- proliferace buněk MeSH
- substrátová specifita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- aorta abdominalis chirurgie MeSH
- cévní protézy MeSH
- kathepsin D biosyntéza MeSH
- proteiny MeSH
- psi MeSH
- tyrosin MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- zvířata MeSH
In this study the levels of auto-antibodies formed against the activation peptide of procathepsin D were determined by the ELISA method using a synthetic multiantigen peptide containing the N-terminal amino acid sequence of the activation peptide of procathepsin D as a coating antigen. Based on the results auto-antibodies cannot be considered suitable cancer markers.
Cathepsin D is an aspartic peptidase involved in cellular processes including proliferation and apoptosis and implicated in human pathologies such as cancer and neurodegeneration. Our knowledge about the relationship between proteolysis and bioactive sphingolipids is still very limited. Here, we describe a complex pattern of modulation of the peptidolytic activity of cathepsin D by sphingolipids. A panel of sphingolipid derivatives was screened in a FRET-based assay; these molecules demonstrated negative or positive modulation of cathepsin D peptidolytic activity, depending on the sphingolipid structure. Certain sphingosines and ceramides inhibited cathepsin D in the submicromolar range, and structural requirements for this inhibitory effect were evaluated. The interaction of cathepsin D with sphingolipids was also demonstrated by fluorescence polarization measurements and determined to follow a competitive inhibition mode. In contrast, monoester phosphosphingolipids, especially ceramide-1-phosphate, were identified as activators of cathepsin D peptidolytic activity at submicromolar concentrations. Thus, sphingolipids and phosphosphingolipids, known to be antagonistic in their cell-signaling functions, displayed opposite modulation of cathepsin D. Sphingolipid-based modulators of cathepsin D are potentially involved in the control of cathepsin D-dependent processes and might serve as a scaffold for the development of novel regulators of this therapeutic target.
- MeSH
- apoptóza účinky léků MeSH
- ceramidy chemie metabolismus farmakologie MeSH
- fluorescenční polarizace MeSH
- fosforylace MeSH
- kathepsin D chemie metabolismus MeSH
- kinetika MeSH
- lidé MeSH
- nádory enzymologie patologie MeSH
- proteolýza účinky léků MeSH
- rezonanční přenos fluorescenční energie MeSH
- sfingosin chemie metabolismus farmakologie MeSH
- signální transdukce účinky léků MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
To identify the gut-associated tick aspartic hemoglobinase, this work focuses on the functional diversity of multiple Ixodes ricinus cathepsin D forms (IrCDs). Out of three encoding genes representing Ixodes scapularis genome paralogs, IrCD1 is the most distinct enzyme with a shortened propeptide region and a unique pattern of predicted post-translational modifications. IrCD1 gene transcription is induced by tick feeding and is restricted to the gut tissue. The hemoglobinolytic role of IrCD1 was further supported by immunolocalization of IrCD1 in the vesicles of tick gut cells. Properties of recombinantly expressed rIrCD1 are consistent with the endo-lysosomal environment because the zymogen is autoactivated and remains optimally active in acidic conditions. Hemoglobin cleavage pattern of rIrCD1 is identical to that produced by the native enzyme. The preference for hydrophobic residues at the P1 and P1' position was confirmed by screening a novel synthetic tetradecapeptidyl substrate library. Outside the S1-S1' regions, rIrCD1 tolerates most amino acids but displays a preference for tyrosine at P3 and alanine at P2'. Further analysis of the cleavage site location within the peptide substrate indicated that IrCD1 is a true endopeptidase. The role in hemoglobinolysis was verified with RNAi knockdown of IrCD1 that decreased gut extract cathepsin D activity by >90%. IrCD1 was newly characterized as a unique hemoglobinolytic cathepsin D contributing to the complex intestinal proteolytic network of mainly cysteine peptidases in ticks.
- MeSH
- genetická transkripce fyziologie MeSH
- genom fyziologie MeSH
- hemoglobiny genetika metabolismus MeSH
- kathepsin D genetika metabolismus MeSH
- klíště enzymologie genetika MeSH
- posttranslační úpravy proteinů fyziologie MeSH
- proteiny členovců genetika metabolismus MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- střeva enzymologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- anafylaxe MeSH
- kathepsin D imunologie MeSH
- modely u zvířat MeSH
- morčata MeSH
- prezentace antigenu MeSH
- Check Tag
- morčata MeSH
