Relationship between prolyl oligopeptidase conformations with its interaction with alfa-synuclein

• Grant number: 17/24049-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2018
• End date: August 31, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Enzymology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Vitor Marcelo Silveira Bueno Brandão de Oliveira
• Grantee: Gabriel Silva Santos Narciso Louredo
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Prolyl Oligopeptidase (POP; EC3.4.21.26) is a serine peptidase present in various tissues and cell types. Some studies show that it is highly expressed in GABAergic and cholinergic interneurons of the thalamus and cortex. A distinguishable POP feature is the cleavage after proline residues in oligopeptides smaller than 3kDa. Recent studies have indicated that the major POP action is on intracellular peptides. The description that the acetyl-SDKP formation is strictly dependent of the POP cleavage of one intracellular oligopeptide precursor supports this role for this peptidase. POP interacts with the ±-synuclein facilitating the nucleation and oligomerization of this protein, but, interestingly POP inhibitors significantly reduce this ±-synuclein oligomerization. Further studies showing that POP inhibitors also protect from death cells that over-express ±-synuclein, placed POP as a new target for synucleinopathies treatment. POP active site in located in a cavity formed in the interface of two domains: the ±, ² catalytic domain and the seven-bladed ²-propeller regulatory domain, which limits the substrate access to the catalytic site. Crystallographic structures and kinetic data indicate that POP may have at least two main conformations: an "open" conformation, which the two protein domains are away from each other exposing the active site and the "closed" conformation, which presents the domains together hiding the active site. Furthermore, active site ligands (substrate or inhibitors) may alter these conformations and/or the possible equilibrium that can exist between these conformations. To study this possible hinge-like (open-close) movement that POP may present due to substrate or inhibitors interactions and the implication of this structural rearrangements on the POP interaction with the ±-synuclein is the main goal of the present project. (AU)