Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations

Abstract

Stimulation or tolerance of natural killer (NK) cells is achieved through a cross-talk of signals derived from cell surface activating and inhibitory receptors. Killer cell immunoglobulin-like receptors (KIR) are a family of highly polymorphic activating and inhibitory receptors that serve as key regulators of human NK cell function. Distinct structural domains in different KIR family members determine function by providing docking sites for ligands or signalling proteins. Here, we review a growing body of literature that has identified important structural elements on KIR that contribute to function through studies of engineered mutants, natural polymorphic sequence variants, crystal structure data and the conservation of protein sequences throughout primate evolution. Extensive natural polymorphism is associated with both human KIR and their ligands, MHC class I (HLA-A, -B and -C) molecules, and numerous studies have demonstrated associations between inheritance of certain combinations of KIR and HLA genes and susceptibility to several diseases, including viral infections, autoimmune disorders and cancers. In addition, certain KIR/HLA combinations can influence pregnancy and the outcome of haematopoietic stem cell transplantation. In view of the significant regulatory influences of KIR on immune function and human health, it is essential to fully understand the impacts of these polymorphic sequence variations on ligand recognition, expression and function of the receptor.

Figure 1

The major structural differences between different killer cell immunoglobulin-like receptor (KIR) family members. The KIR can be divided into three major subgroups: the inhibitory receptors, the activating receptors, and a unique activating receptor known as KIR2DL4. Nomenclature of KIR is based upon the number of extracellular immunoglobulin-like domains (2D or 3D) and the length of the cytoplasmic domain (L for long and S for short). Receptors with long cytoplasmic domains contain one or two immunoreceptor tyrosine-based inhibitory motif sequences (orange) that provide inhibitory function. The short cytoplasmic KIR and the long-tailed KIR2DL4 are activating receptors, which contain a basic amino acid (+) within the transmembrane domain that interacts with an acidic amino acid (−) within the transmembrane domains of signalling adaptor proteins DAP12 (blue) or FcεRI-γ (green), respectively. These adaptors provide intracellular immunoreceptor tyrosine-based activator motif sequences (purple) that allow for activating function.

Figure 2

Alignment of human killer cell immunoglobulin-like receptor (KIR) transmembrane domains. Consensus transmembrane domain sequences are shown for each human KIR, based upon the most common amino acid encoded in all alleles for each gene. Unique amino acids within the activating KIR (2DL4, 2DS, 3DS) are highlighted in bold. Basic amino acids within the transmembrane domains are underlined and in bold type. The dash denotes a gap in the sequence that was introduced for alignment purposes. Although some minor polymorphic substitutions occur within the transmembrane domains of some KIR alleles, they are usually conservative substitutions between similar hydrophobic amino acids. The KIR2DS2*003 sequence, however, contains significant alterations that eliminate the unique lysine and threonine residues found in the activating KIR (bold and italic). Residue positions are numbered at the top. Sequences were derived from the EMBL-EBI Immuno Polymorphism Database (http://www.ebi.ac.uk/ipd/).

Figure 3

Alignment of human killer cell immunoglobulin-like receptor (KIR) cytoplasmic domains. Consensus cytoplasmic domain sequences are shown for each human KIR, based upon the most common amino acid encoded in all alleles for each gene. Sequences were derived from the EMBL-EBI Immuno Polymorphism Database (http://www.ebi.ac.uk/ipd/). Serine/threonine phosphorylation sites (colour-coded and in bold): CK1, casein kinase 1; CK2, casein kinase 2; PKC, protein kinase C; PDK, proline-directed kinase. Immunoreceptor tyrosine-based inhibitory motif and immunoreceptor tyrosine-based switch motif sequences are underlined and in bold.

Figure 4

Alignment of mammalian killer cell immunoglobulin-like receptor (KIR) cytoplasmic domains. Consensus cytoplasmic domain sequences are shown for each KIR, based upon the most common amino acid encoded in all alleles for each gene. Serine/threonine phosphorylation sites (colour-coded and in bold): CK1, casein kinase 1; CK2, casein kinase 2; PKC, protein kinase C; PDK, proline-directed kinase. Immunoreceptor tyrosine-based inhibitory motif, immunoreceptor tyrosine-based switch motif, and related tyrosine-containing sequences are underlined and in bold. The dash denotes a gap inserted into the sequence for alignment purposes. Substitutions in the PDK site that could act as phosphomimetic residues (glutamic acid, E) are underlined. Species designations and sequence sources: human (Homo sapiens) (EMBL-EBI Immuno Polymorphism Database and http://www.uniprot.org); common chimpanzee (Pan troglodytes); pigmy chimpanzee (Pan paniscus); gorilla, Western gorilla (Gorilla gorilla); orangutan, Bornean orangutan (Pongo pygmaeus); rhesus macaque monkey (Mucaca mulatta); African sabaeus monkey (Chlorocebus sabaeus); horse (Equus caballus); cow (Bos taurus); mouse (Mus musculus),; rat (Rattus norvegicus).