title: KIR2DL2/2DL3-E(35) alleles are functionally stronger than -Q(35) alleles.
abstract: KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E(35)) are functionally stronger than those with glutamine at the same position (Q(35)). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E(35) could kill more target cells lacking their ligands than NK cells with the weaker -Q(35) alleles, indicating better licensing of KIR2DL2/L3(+) NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Rafijul
authors.initials: R
authors.lastname: Bari
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Rajoo
authors.initials: R
authors.lastname: Thapa
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D005838:Genotype; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D005973:Glutamine / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D015236:HLA-C Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D061251:Primary Cell Culture; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D054343:Receptors, KIR2DL2 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D054344:Receptors, KIR2DL3 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction
chemical_list: D015236:HLA-C Antigens; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3; D005973:Glutamine; D018698:Glutamic Acid