Antigenic peptide trimming by ER aminopeptidases--insights from structural studies

Abstract

Generation and destruction of antigenic peptides by ER resident aminopeptidases ERAP1 and ERAP2 have been shown in the last few years to be important for the correct functioning and regulation of the adaptive immune response. These two highly homologous aminopeptidases appear to have evolved complex mechanisms well suited for their biological role in antigen presentation. Furthermore, polymorphic variability in these enzymes appears to affect their function and predispose individuals to disease. This review discusses our current understanding of the molecular mechanisms behind ERAP1/2 function as suggested by several recently determined crystallographic structures of these enzymes.

Figure 1

Cartoon representations of known ERAP1/2 crystal structures. Domain I is shown in cyan, domain II in green, domain III in orange and IV in magenta. Note the repositioning of domain IV relative to domains I and II in the “open” versus the “closed” conformations.

Figure 2

Surface representation comparing the “open” to the “closed” ERAP1 and ERAP2 structures. Domains are colored as in figure 1. Cutaway views are shown to allow visualization of the internal cavity of the enzyme. The Zn(II) atom is shown in red. Notice how the internal cavity is open towards the solvent on the top-left edge of each figure.

Figure 3

Surface representations of porcine aminopeptidases N (PDB code 4HOM) and human ERAP1 (PDB code 3MDJ). The structure of aminopeptidases N contains the heptapeptide hormone substance P that was co-crystallized with the enzyme. The same peptide is shown in identical conformation bound onto the known structure of ERAP1.

Figure 4

Atomic interactions between the side-chain of the polymorphic position 528 in ERAP1. Lys528 makes hydrogen bonding interactions with the backbone of Asn414 that resided in helix 4 of domain II. In contrast Arg528 interacts with His548 on domain III as well.

Figure 5

Atomic interactions between the side-chain of the polymorphic position 392 in ERAP2. Asn 392 makes hydrogen bonding interactions with Tyr262. Lys392, approaches the N-terminus of the active-site bound lysine amino acid and makes several salt-bridge interactions with catalytically important Glu residues.