Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 5, Pages 604-U118Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2021
Keywords
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Funding
- Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy
- National Center for Research Resources of the National Institutes of Health
- European Union [017157]
- National Institutes of Health [AI-38996]
- NCSR
- University of Massachusetts Diabetes and Endocrinology Research Center [DK32520]
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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.
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