Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1

Open Access
Publisher Website
Google Scholar
Abstract
Endoplasmic reticulum aminopeptidase 1 (ERAP1) has a crucial role in antigen presentation because it trims peptide ligands to 8–10 residues so that they fit into the peptide-binding groove of MHC class I molecules. The structure of the ERAP1 in complex with bestatin, an aminopeptidase inhibitor, reveals how the enzyme´s catalytic center how the enzyme can preferentially process peptides 10–15 residues long while sparing shorter ones and provides the first evidence that substrate binding induces conformational changes. ERAP1 trims antigen precursors to fit into MHC class I proteins. To fulfill this function, ERAP1 has unique substrate preferences, trimming long peptides but sparing shorter ones. To identify the structural basis for ERAP1's unusual properties, we determined the X-ray crystal structure of human ERAP1 bound to bestatin. The structure reveals an open conformation with a large interior compartment. An extended groove originating from the enzyme's catalytic center can accommodate long peptides and has features that explain ERAP1's broad specificity for antigenic peptide precursors. Structural and biochemical analyses suggest a mechanism for ERAP1's length-dependent trimming activity, whereby binding of long rather than short substrates induces a conformational change with reorientation of a key catalytic residue toward the active site. ERAP1's unique structural elements suggest how a generic aminopeptidase structure has been adapted for the specialized function of trimming antigenic precursors.