PMID- 28559451
OWN - NLM
STAT- MEDLINE
DCOM- 20180312
LR  - 20220129
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 10
IP  - 481
DP  - 2017 May 30
TI  - A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing 
      by enhancing the stability of NKG2D ligand binding.
LID - eaai8904 [pii]
LID - 10.1126/scisignal.aai8904 [doi]
AB  - NKG2D (natural killer group 2, member D) is an activating receptor found on the 
      surface of immune cells, including natural killer (NK) cells, which regulates 
      innate and adaptive immunity through recognition of the stress-induced ligands 
      ULBP1 (UL16 binding protein 1) to ULBP6 and MICA/B. Similar to class I human 
      leukocyte antigen (HLA), these NKG2D ligands have a major histocompatibility 
      complex-like fold and exhibit pronounced polymorphism, which influences human 
      disease susceptibility. However, whereas class I HLA polymorphisms occur 
      predominantly in the alpha1alpha2 groove and affect antigen binding, the effects of most 
      NKG2D ligand polymorphisms are unclear. We studied the molecular and functional 
      consequences of the two major alleles of ULBP6, the most polymorphic ULBP gene, 
      which are associated with autoimmunity and relapse after stem cell 
      transplantation. Surface plasmon resonance and crystallography studies revealed 
      that the arginine-to-leucine polymorphism within ULBP0602 affected the 
      NKG2D-ULBP6 interaction by generating an energetic hotspot. This resulted in an 
      NKG2D-ULBP0602 affinity of 15.5 nM, which is 10- to 1000-fold greater than the 
      affinities of other ULBP-NKG2D interactions and limited NKG2D-mediated 
      activation. In addition, soluble ULBP0602 exhibited high-affinity competitive 
      binding for NKG2D and partially suppressed NKG2D-mediated activation of NK cells 
      by other NKG2D ligands. These effects resulted in a decrease in a range of 
      NKG2D-mediated effector functions. Our results reveal that ULBP polymorphisms 
      affect the strength of human lymphocyte responses to cellular stress signals and 
      may offer opportunities for therapeutic intervention.
CI  - Copyright (c) 2017, American Association for the Advancement of Science.
FAU - Zuo, Jianmin
AU  - Zuo J
AUID- ORCID: 0000-0002-8341-465X
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Willcox, Carrie R
AU  - Willcox CR
AUID- ORCID: 0000-0003-4532-1468
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Mohammed, Fiyaz
AU  - Mohammed F
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Davey, Martin
AU  - Davey M
AUID- ORCID: 0000-0002-3463-3127
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Hunter, Stuart
AU  - Hunter S
AUID- ORCID: 0000-0002-3125-1625
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Khan, Kabir
AU  - Khan K
AUID- ORCID: 0000-0002-5210-2653
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Antoun, Ayman
AU  - Antoun A
AUID- ORCID: 0000-0003-0657-4606
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Katakia, Poonam
AU  - Katakia P
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Croudace, Joanne
AU  - Croudace J
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Inman, Charlotte
AU  - Inman C
AUID- ORCID: 0000-0002-0801-4779
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
FAU - Parry, Helen
AU  - Parry H
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
AD  - Department of Haematology, University Hospital Birmingham, Birmingham B15 2TH, 
      UK.
FAU - Briggs, David
AU  - Briggs D
AUID- ORCID: 0000-0002-6796-7086
AD  - National Health Service Blood and Transplant, Birmingham B15 2SG, UK.
FAU - Malladi, Ram
AU  - Malladi R
AUID- ORCID: 0000-0002-0242-630X
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK.
AD  - Department of Haematology, University Hospital Birmingham, Birmingham B15 2TH, 
      UK.
FAU - Willcox, Benjamin E
AU  - Willcox BE
AUID- ORCID: 0000-0002-6113-2109
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK. p.moss@bham.ac.uk b.willcox@bham.ac.uk.
FAU - Moss, Paul
AU  - Moss P
AUID- ORCID: 0000-0002-6895-1967
AD  - Cancer Immunology and Immunotherapy Centre, Institute of Immunology and 
      Immunotherapy, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 
      2TT, UK. p.moss@bham.ac.uk b.willcox@bham.ac.uk.
AD  - Department of Haematology, University Hospital Birmingham, Birmingham B15 2TH, 
      UK.
LA  - eng
GR  - G9818340/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20170530
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (KLRK1 protein, human)
RN  - 0 (Ligands)
RN  - 0 (Membrane Proteins)
RN  - 0 (NK Cell Lectin-Like Receptor Subfamily K)
RN  - 0 (RAET1L protein, human)
SB  - IM
MH  - Binding, Competitive
MH  - Cell Membrane/metabolism
MH  - Cells, Cultured
MH  - Hematologic Neoplasms/genetics/immunology/metabolism/*pathology
MH  - Histocompatibility Antigens Class I/immunology
MH  - Humans
MH  - Killer Cells, Natural/immunology/metabolism/*pathology
MH  - Ligands
MH  - Membrane Proteins/chemistry/genetics/*metabolism
MH  - NK Cell Lectin-Like Receptor Subfamily K/chemistry/genetics/*metabolism
MH  - *Polymorphism, Genetic
MH  - Protein Conformation
MH  - T-Lymphocytes/immunology/metabolism/*pathology
EDAT- 2017/06/01 06:00
MHDA- 2018/03/13 06:00
CRDT- 2017/06/01 06:00
PHST- 2017/06/01 06:00 [entrez]
PHST- 2017/06/01 06:00 [pubmed]
PHST- 2018/03/13 06:00 [medline]
AID - 10/481/eaai8904 [pii]
AID - 10.1126/scisignal.aai8904 [doi]
PST - epublish
SO  - Sci Signal. 2017 May 30;10(481):eaai8904. doi: 10.1126/scisignal.aai8904.