PMID- 25759384 OWN - NLM STAT- MEDLINE DCOM- 20150619 LR - 20240322 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 290 IP - 16 DP - 2015 Apr 17 TI - The structure of the atypical killer cell immunoglobulin-like receptor, KIR2DL4. PG - 10460-71 LID - 10.1074/jbc.M114.612291 [doi] AB - The engagement of natural killer cell immunoglobulin-like receptors (KIRs) with their target ligands, human leukocyte antigen (HLA) molecules, is a critical component of innate immunity. Structurally, KIRs typically have either two (D1-D2) or three (D0-D1-D2) extracellular immunoglobulin domains, with the D1 and D2 domain recognizing the alpha1 and alpha2 helices of HLA, respectively, whereas the D0 domain of the KIR3DLs binds a loop region flanking the alpha1 helix of the HLA molecule. KIR2DL4 is distinct from other KIRs (except KIR2DL5) in that it does not contain a D1 domain and instead has a D0-D2 arrangement. Functionally, KIR2DL4 is also atypical in that, unlike all other KIRs, KIR2DL4 has both activating and inhibitory signaling domains. Here, we determined the 2.8 A crystal structure of the extracellular domains of KIR2DL4. Structurally, KIR2DL4 is reminiscent of other KIR2DL receptors, with the D0 and D2 adopting the C2-type immunoglobulin fold arranged with an acute elbow angle. However, KIR2DL4 self-associated via the D0 domain in a concentration-dependent manner and was observed as a tetramer in the crystal lattice by size exclusion chromatography, dynamic light scattering, analytical ultracentrifugation, and small angle x-ray scattering experiments. The assignment of residues in the D0 domain to forming the KIR2DL4 tetramer precludes an interaction with HLA akin to that observed for KIR3DL1. Accordingly, no interaction was observed to HLA by direct binding studies. Our data suggest that the unique functional properties of KIR2DL4 may be mediated by self-association of the receptor. CI - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Moradi, Shoeib AU - Moradi S AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Berry, Richard AU - Berry R AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. FAU - Pymm, Phillip AU - Pymm P AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Hitchen, Corinne AU - Hitchen C AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Beckham, Simone A AU - Beckham SA AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Wilce, Matthew C J AU - Wilce MC AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Walpole, Nicholas G AU - Walpole NG AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Clements, Craig S AU - Clements CS AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Reid, Hugh H AU - Reid HH AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and. FAU - Perugini, Matthew A AU - Perugini MA AD - the Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne Victoria 3086 Australia. FAU - Brooks, Andrew G AU - Brooks AG AD - the Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia, and. FAU - Rossjohn, Jamie AU - Rossjohn J AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia, the Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom Jamie.rossjohn@monash.edu. FAU - Vivian, Julian P AU - Vivian JP AD - From the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, and the Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia, Julian.vivian@monash.edu. LA - eng SI - PDB/3WYR PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150310 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (HLA-B Antigens) RN - 0 (HLA-B*57:01 antigen) RN - 0 (HLA-G Antigens) RN - 0 (KIR2DL4 protein, human) RN - 0 (Receptors, KIR2DL4) RN - 0 (Recombinant Proteins) SB - IM MH - Amino Acid Sequence MH - Animals MH - Baculoviridae/genetics/metabolism MH - Cloning, Molecular MH - Crystallography, X-Ray MH - Escherichia coli/genetics/metabolism MH - Gene Expression MH - HLA-B Antigens/*chemistry/genetics/metabolism MH - HLA-G Antigens/*chemistry/genetics/metabolism MH - Models, Molecular MH - Molecular Sequence Data MH - Moths/cytology/metabolism MH - Protein Multimerization MH - Protein Structure, Secondary MH - Protein Structure, Tertiary MH - Receptors, KIR2DL4/*chemistry/genetics/metabolism MH - Recombinant Proteins/chemistry/genetics/metabolism MH - Sequence Alignment PMC - PMC4400354 OTO - NOTNLM OT - Immunoglobulin Fold OT - Natural Killer Cells (NK Cells) OT - Protein Structure OT - Receptor Structure-Function OT - Small Angle X-ray Scattering (SAXS) EDAT- 2015/03/12 06:00 MHDA- 2015/06/20 06:00 PMCR- 2016/04/17 CRDT- 2015/03/12 06:00 PHST- 2014/09/16 00:00 [received] PHST- 2015/03/12 06:00 [entrez] PHST- 2015/03/12 06:00 [pubmed] PHST- 2015/06/20 06:00 [medline] PHST- 2016/04/17 00:00 [pmc-release] AID - S0021-9258(20)42690-0 [pii] AID - M114.612291 [pii] AID - 10.1074/jbc.M114.612291 [doi] PST - ppublish SO - J Biol Chem. 2015 Apr 17;290(16):10460-71. doi: 10.1074/jbc.M114.612291. Epub 2015 Mar 10.