Mechanism of Action of Prolyl Oligopeptidase (PREP) in Degenerative Brain Diseases: Has Peptidase Activity Only a Modulatory Role on the Interactions of PREP with Proteins?

Abstract

In the aging brain, the correct balance of neural transmission and its regulation is of particular significance, and neuropeptides have a significant role. Prolyl oligopeptidase (PREP) is a protein highly expressed in brain, and evidence indicates that it is related to aging and in neurodegenration. Although PREP is regarded as a peptidase, the physiological substrates in the brain have not been defined, and after intense research, the molecular mechanisms where this protein is involved have not been defined. We propose that PREP functions as a regulator of other proteins though peptide gated direct interaction. We speculate that, at least in some processes where PREP has shown to be relevant, the peptidase activity is only a consequence of the interactions, and not the main physiological activity.

Keywords: aging neuroscience; neurodegeneration; neuropeptides; prolyl oligopeptidase; proten-protein interactions.

Figure 1

3-Dimentional model of porcine PREP based on its crystal structure (Fülöp et al., , ; Rea and Fülöp, 2011). The figure shows the catalytic domain (α/β-hydrolase fold) and the propeller domain (7-bladed β-propeller fold).

Figure 2

A proposed functional cycle for PREP. PREP in an active form (A) can bind a substrate peptide (S) to become the form A-S. This form is prone to produce a conformational change in PREP, depicted as a red area, becoming A^*-S. This is a stable complex driving the equilibrium A to A-S to the formation of A-S. The A^*-S form, due to the particular conformation, is now able to interact with a protein partner (P) forming a tertiary complex A^*-S-P, which is the biologically active form. The tertiary complex A^*-S-P can be broken by substrate cleavage, regenerating the form A, with low affinity by the partner P. The form active A can be deactivated by interaction with an endogenous inhibitor (EI) or/and reactive oxidative species (ROS). The form A^*-S could slowly lead to substrate cleavage.