The Structure of the Atypical Killer Cell Immunoglobulin-like Receptor, KIR2DL4

被引:33
|
作者
Moradi, Shoeib [1 ]
Berry, Richard [1 ,2 ]
Pymm, Phillip [1 ]
Hitchen, Corinne [1 ]
Beckham, Simone A. [1 ]
Wilce, Matthew C. J. [1 ]
Walpole, Nicholas G. [1 ]
Clements, Craig S. [1 ]
Reid, Hugh H. [1 ]
Perugini, Matthew A. [3 ]
Brooks, Andrew G. [4 ]
Rossjohn, Jamie [1 ,2 ,5 ]
Vivian, Julian P. [1 ,2 ]
机构
[1] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia
[2] Monash Univ, Australian Res Council Ctr Excellence Adv Mol Ima, Clayton, Vic 3800, Australia
[3] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem, Melbourne, Vic 3086, Australia
[4] Univ Melbourne, Peter Doherty Inst Infect & Immun, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia
[5] Cardiff Univ, Inst Infect & Immun, Sch Med, Cardiff CF14 4XN, S Glam, Wales
基金
澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;
关键词
Immunoglobulin Fold; Natural Killer Cells (NK Cells); Protein Structure; Receptor Structure-Function; Small Angle X-ray Scattering (SAXS); SIZE-DISTRIBUTION ANALYSIS; CRYSTAL-STRUCTURE; HLA-G; ACTIVATING RECEPTOR; CUTTING EDGE; NK CELLS; RECOGNITION; CD158D; EXPRESSION; ULTRACENTRIFUGATION;
D O I
10.1074/jbc.M114.612291
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: KIR2DL4 is an important natural killer cell receptor with properties distinct from other KIRs. Results: The D0 domain of KIR2DL4 drove self-association of the receptor. Conclusion: Among KIRs, the self-association of KIR2DL4 is unique and a result of discrete differences in its D0 domain. Significance: The self-association of KIR2DL4 has implications for its unique signaling and function. 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 1 and 2 helices of HLA, respectively, whereas the D0 domain of the KIR3DLs binds a loop region flanking the 1 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 angstrom 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.
引用
收藏
页码:10460 / 10471
页数:12
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