Abstract
Upon engagement of specific class I major histocompatibility complex (MHC) molecules on target cells, inhibitory receptors on natural killer (NK) cells deliver a negative signal that prevents the target cell lysis by NK cells. In humans, killer cell immunoglobulin-related receptors (KIR) with two immunoglobulin-like domains (KIR2D) modulate the lysis of target cells bearing specific HLA-C alleles (Moretta, A., Vitale, M., Bottino, C., Orengo, A. M., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., and Moretta, L. (1993) J. Exp. Med. 178, 597-604). The transduction of inhibitory signals by KIR2D molecules is impaired by the zinc chelator, 1,10-phenanthroline, and mutation of a putative zinc-binding site (Rajagopalan, S., and Long, E. O. (1998) J. Immunol. 161, 1299-1305), but the mechanism by which zinc may affect the function of KIR remains unknown. In this study, the inhibitory NK receptor KIR2DL1 was discovered to dimerize in the presence of Co(2+) as observed on native gel electrophoresis and by gel filtration column chromatography. Furthermore, Co(2+)-mediated KIR2DL1 dimer binds to HLA-Cw4 with higher affinity than the wild type KIR2DL1 monomer. Replacement of the amino-terminal His residue by Ala abolishes the ability of KIR2DL1 to bind Co(2+), indicating that Co(2+)-mediated KIR2DL1 dimerization involves pairing of the D1 domain. Although not observed on native gels, the inhibitory receptor KIR2DL1 can be chemically cross-linked into dimers in the presence of Zn(2+) and its related divalent metal ions, suggesting that Co(2+)-mediated dimerization of KIR2DL1 may mimic a weaker interaction between KIR2DL1 and zinc in vivo.
Highlights
Natural killer (NK)1 cells express an array of inhibitory and activating receptors on the cell surface that control their cytotoxicity
We demonstrate that the extracellular domain of the inhibitory NK receptor KIR2DL1 dimerizes in the presence of Co2ϩ
The extracellular domain of the inhibitory NK receptor KIR2DL1 dimerizes in the presence of Co2ϩ as demonstrated by native and SDS-gel electrophoresis as well as gel filtration chromatography
Summary
Vol 275, No 31, Issue of August 4, pp. 23700 –23706, 2000 Printed in U.S.A. Cobalt-mediated Dimerization of the Human Natural Killer Cell Inhibitory Receptor*. Killer cell immunoglobulin-related receptors (KIR) with two immunoglobulin-like domains (KIR2D) modulate the lysis of target cells bearing specific HLA-C alleles The activating KIR molecules have similar extracellular domain structures as the inhibitory receptors, but lack the immunoreceptor tyrosinebased inhibition motifs in their cytoplasmic domains and contain a positively charged Lys residue in their transmembrane segments KIR2DL molecules contain a putative zinc-binding motif (HEXXH) sequence [6], HEGVH (residues 1–5), in their extracellular domains, suggesting that zinc plays a role in the structure and function of KIR2D. Mutation of the His residues in the amino-terminal zinc motif (HEGVH) impairs the ability of a KIR2D molecule to deliver inhibitory signals but not its ability to bind HLA-C [8].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
