Molecular architecture of the major histocompatibility complex class I-binding site of Ly49 natural killer cell receptors.

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TitleMolecular architecture of the major histocompatibility complex class I-binding site of Ly49 natural killer cell receptors.
Publication TypeJournal Article
Year of Publication2008
AuthorsDeng, L, Cho, S, Malchiodi, EL, Kerzic, MC, Dam, J, Mariuzza, RA
JournalJ Biol Chem
Volume283
Issue24
Pagination16840-9
Date Published2008 Jun 13
ISSN0021-9258
KeywordsAmino Acid Sequence, Antigens, Ly, Binding Sites, Crystallography, X-Ray, Dimerization, Gene Expression Regulation, Histocompatibility Antigens Class I, Humans, Killer Cells, Natural, Kinetics, Lectins, C-Type, Models, Molecular, Molecular Conformation, Molecular Sequence Data, Protein Binding, Receptors, NK Cell Lectin-Like, Sequence Homology, Amino Acid
Abstract

Natural killer (NK) cells play a vital role in the detection and destruction of virally infected and tumor cells during innate immune responses. The highly polymorphic Ly49 family of NK receptors regulates NK cell function by sensing major histocompatibility complex class I (MHC-I) molecules on target cells. Despite the determination of two Ly49-MHC-I complex structures, the molecular features of Ly49 receptors that confer specificity for particular MHC-I alleles have not been identified. To understand the functional architecture of Ly49-binding sites, we determined the crystal structures of Ly49C and Ly49G and completed refinement of the Ly49C-H-2K(b) complex. This information, combined with mutational analysis of Ly49A, permitted a structure-based classification of Ly49s that we used to dissect the binding site into three distinct regions, each having different roles in MHC recognition. One region, located at the center of the binding site, has a similar structure across the Ly49 family and mediates conserved interactions with MHC-I that contribute most to binding. However, the preference of individual Ly49s for particular MHC-I molecules is governed by two regions that flank the central region and are structurally more variable. One of the flanking regions divides Ly49s into those that recognize both H-2D and H-2K versus only H-2D ligands, whereas the other discriminates among H-2D or H-2K alleles. The modular design of Ly49-binding sites provides a framework for predicting the MHC-binding specificity of Ly49s that have not been characterized experimentally.

DOI10.1074/jbc.M801526200
Alternate JournalJ. Biol. Chem.
PubMed ID18426793
PubMed Central IDPMC2423261
Grant ListAI047990 / AI / NIAID NIH HHS / United States
R01 AI047990-08 / AI / NIAID NIH HHS / United States