NDLI: Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Mpakali, Anastasia Saridakis, Emmanuel Giastas, Petros Mavridis, Irene M. Stratikos, Efstratios Mathioudakis, Nikolas
Description	Author Affiliation: Mpakali A ( From the National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece.); Giastas P ( From the National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece.); Mathioudakis N ( From the National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece.); Mavridis IM ( From the National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece.); Saridakis E ( From the National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece e.saridakis@inn.demokritos.gr.); Stratikos E ( From the National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece stratos@rrp.demokritos.gr stratikos@gmail.com.)
Abstract	Endoplasmic reticulum (ER) 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 2.5 and 2.7 Å, respectively, and compared them to the apo-form structure determined to 3.0 Å. 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 toward 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 toward 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.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	43
Volume Number	290
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2015-10-23
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Aminopeptidases Metabolism Antigens Endoplasmic Reticulum Enzymology Peptides Chemistry Animals Cell Line Crystallography Models, Molecular Protein Conformation Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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