The role of D0 is even less well defined, but this domain has been shown to be necessary in the binding of KIR3DL1 to HLA-B*5101 (24)

The role of D0 is even less well defined, but this domain has been shown to be necessary in the binding of KIR3DL1 to HLA-B*5101 (24). the first evidence for the direct binding of a KIR3DS1+ cells to HLA-Bw4, and highlights the key role for position 138 in determining ligand specificity of KIR3DS1. They also reveal that KIR3DS1 reactivity and specificity is usually dictated by complex interactions between the residues in this region, suggesting a unique functional development of KIR3DS1 within the activating KIR family. Introduction The Killer Immunoglobulin-like Receptor (KIR) family of Natural Killer (NK) receptors consists of 14 users including receptors with both inhibitory and activating potential (1). This family shows a high degree of variance among populations, including variance in gene content, at the level of allelic polymorphism and the frequency and SU 5416 (Semaxinib) level of expression (2C4). Several of the KIR are known to bind to Human Leukocyte Antigen (HLA) class I molecules. KIR2DL1 and KIR2DL2/3 identify HLA-C2 and C1 respectively (5), KIR3DL2 recognizes A*3 and A*11 allotypes (6), KIR2DL4 is usually reported to bind to HLA-G (7), while KIR3DL1 recognizes HLA-A or -B molecules expressing the Bw4 epitope (8). Activating users of the KIR family, which show a high Rabbit Polyclonal to IL-2Rbeta (phospho-Tyr364) degree of sequence similarity in the extracellular portion to inhibitory users, also bind to HLA, albeit with much lower affinity (9C11). Acknowledgement of HLA-Bw4 by KIR3DL1 allotypes is usually well characterized, with sequence variance in the KIR3DL1 molecule, the Bw4 molecule and the sequence of peptide offered by the Bw4 molecule all influencing the conversation (12C15). There is also growing evidence that KIR3DS1 may recognize HLA-Bw4. Several genetic studies have correlated the presence of both KIR3DS1 and HLA-Bw4 with the outcome of SU 5416 (Semaxinib) disease (16). In particular in HIV contamination, it has been shown that this epistatic conversation of KIR3DS1 and a subgroup of Bw4 SU 5416 (Semaxinib) transporting isoleucine at position 80 (Bw4-80I) delays progression to AIDS, reducing viral weight early as well as leading to a reduction in opportunistic infections later in disease (17, 18). Functional evidence to support the conversation of KIR3DS1 and HLA-Bw4, at least in the context of HIV contamination, comes from the statement that KIR3DS1+ NK cells can suppress HIV replication and lyse SU 5416 (Semaxinib) HIV+ target cells in a Bw4-dependent manner (19). However, several attempts to characterize the direct conversation of KIR3DS1 with Bw4 have been unsuccessful C traditional Bw4+ target cell lines are not killed in a KIR3DS1-dependent manner and HLA-Bw4 tetramers do not bind to KIR3DS1-expressing cells, even those tetramers that present HIV-derived peptides (13, 20, 21). The highly polymorphic KIR3DL1 gene locus is unique in the KIR family in encoding both inhibitory (KIR3DL1) and activating (KIR3DS1) allotypes. The SU 5416 (Semaxinib) 3D KIR contain three extracellular Ig domains termed D0 (membrane distal), D1 and D2 (membrane proximal). Each of these domains is usually encoded by a separate exon, exons 3, 4, and 5 respectively of the KIR3DL1 gene (22). The D1 and D2 domains of KIR3DL1 are homologous to the 2 2 Ig domains of type I 2D KIR (2DL1, 2, and 3) which contain a D1 and D2 but have a pseudoexon in place of exon 3. Type II 2D KIR (2DL4 and 2DL5) contain a D0 and D2 configuration. The structure of the conversation of type I 2D KIR with their HLA-C ligands has been resolved and shown to be dependent on residues from both D1 and D2 (23). While no structure of a 3D KIR, either alone or in association with HLA has been resolved, a.

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