title: Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Tina T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Chang
authors.forename: Irini
authors.initials: I
authors.lastname: Evnouchidou
authors.forename: Ian A
authors.initials: IA
authors.lastname: York
authors.forename: Christos
authors.initials: C
authors.lastname: Zikos
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.forename: Efstratios
authors.initials: E
authors.lastname: Stratikos
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000626:Aminopeptidases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000941:Antigens; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human; D007930:Leucine; C012211:ubenimex