NDLI: Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Papakyriakou, Athanasios Stratikos, Efstratios Harlos, Karl Zhao, Yuguang Georgiadis, Dimitris Mpakali, Anastasia Saridakis, Emmanuel Kokkala, Paraskevi
Description	Author Affiliation: Mpakali A ( National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece); Saridakis E ( National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece); Harlos K ( Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, United Kingdom); Zhao Y ( Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, United Kingdom); Papakyriakou A ( National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece); Kokkala P ( National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece); Georgiadis D ( Department of Chemistry, University of Athens, Athens 15771, Greece.); Stratikos E ( National Center for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece)
Abstract	Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast number of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that prepares antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent. The N-terminal moiety of the peptide is located at the active site, positioned optimally for catalysis, whereas the C-terminal moiety of the peptide is stabilized along the extended internal cavity lodged between domains II and IV. Hydrophobic interactions and shape complementarity enhance peptide affinity beyond the catalytic site and support a limited selectivity model for antigenic peptide selection that may underlie the generation of complex immunopeptidomes.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	6
Volume Number	195
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2015-09-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Antigens Immunology Cystinyl Aminopeptidase Ultrastructure Epitopes Animals Catalytic Domain Genetics Cell Line Crystallography, X-ray Metabolism Dendritic Cells Hek293 Cells Hydrophobic And Hydrophilic Interactions Insects Cytology Models, Molecular Molecular Dynamics Simulation Protein Binding Physiology Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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