| Grant number: | 18/09158-0 |
| Support Opportunities: | Regular Research Grants |
| Start date: | August 01, 2018 |
| End date: | October 31, 2020 |
| Field of knowledge: | Biological Sciences - Biochemistry - Enzymology |
| Principal Investigator: | Vitor Marcelo Silveira Bueno Brandão de Oliveira |
| Grantee: | Vitor Marcelo Silveira Bueno Brandão de Oliveira |
| Host Institution: | Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil |
| Associated researchers: | Emer Suavinho Ferro ; Jair Ribeiro Chagas ; Marcelo Ferreira Marcondes Machado ; Paulo Cezar de Almeida |
Abstract
Prolyl oligopeptidase (POP; EC 3.4.21.26) is a serine-peptidase present in various types of cells and tissues. Some studies have shown that POP is highly expressed in GABAergic and cholinergic interneurons from the thalamus and cortex. A distinguish feature of POP is its determined substrate specificity: POP hydrolyses peptide bonds after proline residues and only in oligopeptides with less than 3kDa. POP-like activity can be detected in extracellular fluids (plasma for example) where it can take place in the metabolism of bioactive peptides as: substance-P (SP); arginine-vasopressin (AVP) and thyrotropin-releasing hormone (TRH). However, most of the POP is found in the cytoplasm since it has not the signal sequence and, so far, there is no an identified mechanism for explain the POP secretion. Recent studies have revealed intracellular POP substrates and, the identification of the acetyl-SDKP as a POP product was a major finding in this regard. POP interacts with the alpha-synuclein facilitating the nucleation and further oligomerization of this protein but, interestingly this process is very reduced when POP is inhibited. It is important to emphasize that the alpha-synuclein is not a POP substrate. These findings and further studies showing that POP inhibitors diminish the death of alpha-synuclein over expressing cells put the POP as a new target for treatment of the called synucleinopathies. The POP active site is located at the interfaced between two domains: the alpha, beta catalytic domain and the regulatory domain (seven-bladed propeller domain) which limits the size of the substrate that can reach the active site of this enzyme to oligopeptides of less than 3kDa. Crystallographic structures and kinetic data show that POP presents an "opened" conformation (the two domains are distant and the entrance for the active site is exposed) and a "closed" conformation (the two domains approximate closing the entrance for the active site), and, active site ligands (substrates or inhibitors) can change the possible equilibrium existent between these two conformations. The main goal of the present project is to study this possible "open-close" movement that the POP molecule can undergo upon interaction with its substrates and inhibitors, with emphasis in the implications that this conformational alteration can have in the POP interaction with the alpha-synuclein. The unconventional POP cell secretion mechanism(s) will also be studied, since, so far there is no clear explanations for this process and consequently the highly cited importance of the extracellular POP actions, as above mentioned. (AU)
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