The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

Abstract

<jats:p>Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.</jats:p>

Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease

“…Therefore, we provide new insights of the role of position 238 in KIR3DL1 and suggest the associations of these two allotypes with different PD symptoms could be the result of functional differences of these two molecules caused by the change G238R. These findings are in accordance with recent experimental work by Saunders et al (65), which demonstrates that allelic variation in KIR3DL1 results in functional differences impacting the ability of the receptor to interact with HLA.…”

High-Resolution Characterization of KIR Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity

“…To confirm the sequences of novel variants, we used the Sanger method to resequence individuals carrying any possible novel SNV in KIR2DL1 and KIR3DL1S1. While confirmation of all novel variants was out of scope for the current project, we selected these loci as exemplars for this work due to substantial previous work examining their structure and function (25,56,61,(65)(66)(67)(68)(69)(70)(71), including the availability of crystal for molecular modeling structures (57,(72)(73)(74)(75)(76). In future work we will continue to explore novel variants that were detected at other loci during this study.…”

Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C

“…We determined the crystal structure of KIR2DL2 in complex with HLA-C*07:02 presenting a self-peptide derived from histone H3 (RL9, residues 40-48, RYRPGTVAL) 29 . To date, crystal structures of KIR2DL1, KIR2DL2, KIR2DS2 with single HLA allotypes as well as KIR3DL1 in complex HLA-B*57:01 and -B*57:03 have been determined 24,25,30,31 . The structure of KIR2DL2 in complex with HLA-C*03:04-GAVDPLLAL (GL9) was previously determined 24 , and together with our structure of KIR2DL2 in complex with HLA-C*07:02-RL9 provided an opportunity to compare how allelically related KIR2D recognise distinct HLA-I allotypes (Figs.…”