Publication Date:
2011-10-25
Description:
Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0-D1-D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies. Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards beta2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an 'innate HLA sensor' domain. Second, whereas the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1-pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723390/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723390/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vivian, Julian P -- Duncan, Renee C -- Berry, Richard -- O'Connor, Geraldine M -- Reid, Hugh H -- Beddoe, Travis -- Gras, Stephanie -- Saunders, Philippa M -- Olshina, Maya A -- Widjaja, Jacqueline M L -- Harpur, Christopher M -- Lin, Jie -- Maloveste, Sebastien M -- Price, David A -- Lafont, Bernard A P -- McVicar, Daniel W -- Clements, Craig S -- Brooks, Andrew G -- Rossjohn, Jamie -- G0501963/Medical Research Council/United Kingdom -- ZIA AI001026-04/Intramural NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Oct 23;479(7373):401-5. doi: 10.1038/nature10517.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22020283" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Binding Sites/genetics
;
HLA-B Antigens/*chemistry/genetics/*immunology
;
Humans
;
Models, Molecular
;
Mutant Proteins/chemistry/genetics/immunology
;
Polymorphism, Genetic/genetics
;
Protein Structure, Tertiary
;
Receptors, KIR3DL1/*chemistry/genetics/*immunology
;
Structure-Activity Relationship
;
beta 2-Microglobulin/chemistry/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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