| Structural highlights
Function
[ERAP2_HUMAN] Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Preferentially hydrolyzes the basic residues Arg and Lys.[1] [2] [3]
Publication Abstract from PubMed
Endoplasmic reticulum aminopeptidases process antigenic peptide precursors to generate epitopes for presentation by MHC class I molecules and help shape the antigenic peptide repertoire and cytotoxic T-cell responses. To perform this function, ER aminopeptidases have to recognize and process a vast variety of peptide sequences. To understand how these enzymes recognize substrates, we determined crystal structures of ER aminopeptidase 2 (ERAP2) in complex with a substrate analogue and a peptidic product to 2.5A and 2.7A respectively and compared them to the apo form structure determined to 3.0A. The peptides were found within the internal cavity of the enzyme with no direct access to the outside solvent. The substrate analogue extends away from the catalytic center towards the distal end of the internal cavity making interactions with several shallow pockets along the path. A similar configuration was evident for the peptidic product although decreasing electron density towards its C-terminus indicated progressive disorder. Enzymatic analysis confirmed that visualized interactions can either positively or negatively impact in vitro trimming rates. Opportunistic side-chain interactions and lack of deep specificity pockets support a limited-selectivity model for antigenic peptide processing by ERAP2. In contrast to proposed models for the homologous ERAP1, no specific recognition of the peptide C-terminus by ERAP2 was evident, consistent with functional differences in length selection and self-activation between these two enzymes. Our results suggest that ERAP2 selects substrates by sequestering them in its internal cavity and allowing opportunistic interactions to determine trimming rates, thus combining substrate permissiveness with sequence bias.
Structural basis for antigenic peptide recognition and processing by ER aminopeptidase 2.,Mpakali A, Giastas P, Mathioudakis N, Mavridis IM, Saridakis E, Stratikos E J Biol Chem. 2015 Sep 17. pii: jbc.M115.685909. PMID:26381406[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tanioka T, Hattori A, Masuda S, Nomura Y, Nakayama H, Mizutani S, Tsujimoto M. Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases. J Biol Chem. 2003 Aug 22;278(34):32275-83. Epub 2003 Jun 10. PMID:12799365 doi:http://dx.doi.org/10.1074/jbc.M305076200
- ↑ Saveanu L, Carroll O, Lindo V, Del Val M, Lopez D, Lepelletier Y, Greer F, Schomburg L, Fruci D, Niedermann G, van Endert PM. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005 Jul;6(7):689-97. Epub 2005 May 22. PMID:15908954 doi:http://dx.doi.org/10.1038/ni1208
- ↑ Chang SC, Momburg F, Bhutani N, Goldberg AL. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17107-12. Epub 2005 Nov 14. PMID:16286653 doi:http://dx.doi.org/0500721102
- ↑ Mpakali A, Giastas P, Mathioudakis N, Mavridis IM, Saridakis E, Stratikos E. Structural basis for antigenic peptide recognition and processing by ER aminopeptidase 2. J Biol Chem. 2015 Sep 17. pii: jbc.M115.685909. PMID:26381406 doi:http://dx.doi.org/10.1074/jbc.M115.685909
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