Structural Basis For Antigenic Peptide Precursor Processing by the Endoplasmic Reticulum Aminopeptidase ERAP1

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Nature Structural and Molecular Biology

DOI:https://doi.org/10.1038/nsmb.2021· OSTI ID:1041963

Nguyen, T; Chang, S; Evnouchidou, I; York, I; Zikos, C; Rock, K; Goldberg, A; Stratikos, E; Stern, L

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.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041963
• Report Number(s): BNL--97641-2012-JA
• Journal Information: Nature Structural and Molecular Biology, Journal Name: Nature Structural and Molecular Biology Journal Issue: 5 Vol. 18; ISSN 1545-9993
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AMINOPEPTIDASES
ANTIGENS
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
ENDOPLASMIC RETICULUM
PEPTIDES
PRECURSOR
PROCESSING
PROTEINS
RESIDUES
SPECIFICITY
SUBSTRATES