Is There an Interplay Between the Functional Domains of IRAP?

Abstract

As a member of the M1 family of aminopeptidases, insulin regulated aminopeptidase (IRAP) is characterized by distinct binding motifs at the active site in the C-terminal domain that mediate the catalysis of peptide substrates. However, what makes IRAP unique in this family of enzymes is that it also possesses trafficking motifs at the N-terminal domain which regulate the movement of IRAP within different intracellular compartments. Research on the role of IRAP has focused predominantly on the C-terminus catalytic domain in different physiological and pathophysiological states ranging from pregnancy to memory loss. Many of these studies have utilized IRAP inhibitors, that bind competitively to the active site of IRAP, to explore the functional significance of its catalytic activity. However, it is unknown whether these inhibitors are able to access intracellular sites where IRAP is predominantly located in a basal state as the enzyme may need to be at the cell surface for the inhibitors to mediate their effects. This property of IRAP has often been overlooked. Interestingly, in some pathophysiological states, the distribution of IRAP is altered. This, together with the fact that IRAP possesses trafficking motifs, suggest the localization of IRAP may play an important role in defining its physiological or pathological functions and provide insights into the interplay between the two functional domains of the protein.

Keywords: Angiotensin IV; IRAP; IRAP inhibitors; M1 aminopeptidase; pathophysiology; trafficking.

FIGURE 1

Structure of the two functional domains of IRAP: the cytosolic N-terminal domain which contains trafficking motifs and the extracellular C-terminal domain where the catalytic site is found.

FIGURE 2

Key roles of the two functional domains of IRAP. IRAP is predominantly localized in specialized endosomes with a small proportion of IRAP-containing vesicles slowly recycling to the plasma membrane. This movement is regulated by the binding of interacting proteins to the N-terminal domain of IRAP. At the plasma membrane, the catalytic C-terminus of IRAP is exteriorized and therefore has access to cleave a range of peptide substrates.