title: Zinc-Induced Polymerization of Killer-Cell Ig-like Receptor into Filaments Promotes Its Inhibitory Function at Cytotoxic Immunological Synapses.
abstract: The inhibitory function of killer cell immunoglobulin-like receptors (KIR) that bind HLA-C and block activation of human natural killer (NK) cells is dependent on zinc. We report that zinc induced the assembly of soluble KIR into filamentous polymers, as detected by electron microscopy, which depolymerized after zinc chelation. Similar KIR filaments were isolated from lysates of cells treated with zinc, and membrane protrusions enriched in zinc were detected on whole cells by scanning electron microscopy and imaging mass spectrometry. Two independent mutations in the extracellular domain of KIR, away from the HLA-C binding site, impaired zinc-driven polymerization and inhibitory function. KIR filaments formed spontaneously, without the addition of zinc, at functional inhibitory immunological synapses of NK cells with HLA-C(+) cells. Adding to the recent paradigm of signal transduction through higher order molecular assemblies, zinc-induced polymerization of inhibitory KIR represents an unusual mode of signaling by a receptor at the cell surface.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors.forename: Sumati
authors.initials: S
authors.lastname: Rajagopalan
authors.affiliation: Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD 20852, USA.
authors.forename: Pabak
authors.initials: P
authors.lastname: Sarkar
authors.affiliation: Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dorward
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Peterson
authors.affiliation: National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD 20892, USA.
authors.forename: Hsien-Shun
authors.initials: HS
authors.lastname: Liao
authors.affiliation: Center for NanoImaging, Brigham and Women's Hospital, Cambridge, MA 02138, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston MA, 02115, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Guillermier
authors.affiliation: Center for NanoImaging, Brigham and Women's Hospital, Cambridge, MA 02138, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston MA, 02115, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Steinhauser
authors.affiliation: Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD 20852, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Vogel
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA. Electronic address: elong@nih.gov.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Long
mesh_terms: D002478:Cells, Cultured; D057809:HEK293 Cells; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D058105:Polymerization; D054340:Receptors, KIR / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015032:Zinc / Q000494:pharmacology*
chemical_list: D006680:HLA Antigens; D054340:Receptors, KIR; D015032:Zinc
keywords: filament; inhibition; natural killer cell; signaling; zinc