S1 pocket of glutamate carboxypeptidase II: A new binding site for amyloid-β degradation
| Autor: | Min-Ju Kim, Youhoon Cheong, Sangmee Ahn Jo, Hyunyoung Kim, Suk Kyung Lee, Hyung-Seop Youn, Sang Ick Park |
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| Rok vydání: | 2013 |
| Předmět: |
Glutamate Carboxypeptidase II
Amyloid β Amyloid beta Biophysics Glutamic Acid Mice Transgenic Biochemistry Mice Hydrolysis Organophosphorus Compounds Alzheimer Disease Cell Line Tumor Glutamate carboxypeptidase II Animals Humans Enzyme Inhibitors Binding site Molecular Biology Physiological function Amyloid beta-Peptides Binding Sites biology Chemistry Mutagenesis Dipeptides Cell Biology Molecular Docking Simulation Proteolysis Mutagenesis Site-Directed biology.protein Degradation (geology) |
| Zdroj: | Biochemical and Biophysical Research Communications. 438:765-771 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2013.07.059 |
| Popis: | We recently reported that glutamate carboxypeptidase II (GCPII) has a new physiological function degrading amyloid-β (Aβ), distinct from its own hydrolysis activity in N-acetyl-L-aspartyl-L-glutamate (NAAG); however, its underlying mechanism remains undiscovered. Using site-directed mutagenesis and S1 pocket-specific chemical inhibitor (compound 2), which was developed for the present study based on in sillico computational modeling, we discovered that the Aβ degradation occurs through S1 pocket but not through S1′ pocket responsible for NAAG hydrolysis. Treatment with compound 2 prevented GCPII from Aβ degradation without any impairment in NAAG hydrolysis. Likewise, 2-PMPA (specific GCPII inhibitor developed targeting S1′ pocket) completely blocked the NAAG hydrolysis without any effect on Aβ degradation. Pre-incubation with NAAG and Aβ did not affect Aβ degradation and NAAG hydrolysis, respectively. These data suggest that GCPII has two distinctive binding sites for two different substrates and that Aβ degradation occurs through binding to S1 pocket of GCPII. |
| Databáze: | OpenAIRE |
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