Structure of natural killer receptor 2B4 bound to CD48 reveals basis for heterophilic recognition in signaling lymphocyte activation molecule family.
Natural killer (NK) cells eliminate virally infected and tumor cells. Among the receptors regulating NK cell function is 2B4 (CD244), a member of the signaling lymphocyte-activation molecule (SLAM) family that binds CD48. 2B4 is the only heterophilic receptor of the SLAM family, whose other members, e.g., NK-T-B-antigen (NTB-A), are self-ligands. We determined the structure of the complex between the N-terminal domains of mouse 2B4 and CD48, as well as the structures of unbound 2B4 and CD48. The complex displayed an association mode related to, yet distinct from, that of the NTB-A dimer. Binding was accompanied by the rigidification of flexible 2B4 regions containing most of the polymorphic residues across different species and receptor isoforms. We propose a model for 2B4-CD48 interactions that permits the intermixing of SLAM receptors with major histocompatibility complex-specific receptors in the NK cell immune synapse. This analysis revealed the basis for heterophilic recognition within the SLAM family.
Velikovsky
C Alejandro
CA
Center for Advanced Research in Biotechnology, W.M. Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, MD 20850, USA.
Deng
Lu
L
Chlewicki
Lukasz K
LK
Fernández
Marisa M
MM
Kumar
Vinay
V
Mariuzza
Roy A
RA
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000071178:CD48 Antigen; D018360:Crystallography, X-Ray; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry* / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D008969:Molecular Sequence Data; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family
D015703:Antigens, CD; D000071178:CD48 Antigen; C000604065:CD48 protein, human; C490007:Cd244a protein, mouse; C000604066:Cd48 protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family