A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D-ligand binding

2.50
Hdl Handle:
http://hdl.handle.net/2436/620507
Title:
A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D-ligand binding
Authors:
Zuo, Jianmin; Willcox, Carrie R; Mohammed, Fiyaz; Davey, Martin; Hunter, Stuart; Khan, Kabir; Antoun, Ayman ( 0000-0003-0657-4606 ) ; Katakia, Poonam; Croudace, Joanne; Inman, Charlotte; Parry, Helen; Briggs, David; Malladi, Ram; Willcox, Benjamin E; Moss, Paul
Abstract:
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 α1α2 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.
Publisher:
American Association for the Advancement of Science
Journal:
Science Signaling
Issue Date:
May-2017
URI:
http://hdl.handle.net/2436/620507
Additional Links:
http://stke.sciencemag.org/content/10/481/eaai8904
Type:
Article
Language:
en
ISSN:
1945-0877
Sponsors:
Leukaemia and Lymphoma Research
Appears in Collections:
FSE

Full metadata record

DC FieldValue Language
dc.contributor.authorZuo, Jianminen
dc.contributor.authorWillcox, Carrie Ren
dc.contributor.authorMohammed, Fiyazen
dc.contributor.authorDavey, Martinen
dc.contributor.authorHunter, Stuarten
dc.contributor.authorKhan, Kabiren
dc.contributor.authorAntoun, Aymanen
dc.contributor.authorKatakia, Poonamen
dc.contributor.authorCroudace, Joanneen
dc.contributor.authorInman, Charlotteen
dc.contributor.authorParry, Helenen
dc.contributor.authorBriggs, Daviden
dc.contributor.authorMalladi, Ramen
dc.contributor.authorWillcox, Benjamin Een
dc.contributor.authorMoss, Paulen
dc.date.accessioned2017-06-09T09:35:02Z-
dc.date.available2017-06-09T09:35:02Z-
dc.date.issued2017-05-
dc.identifier.issn1945-0877en
dc.identifier.urihttp://hdl.handle.net/2436/620507-
dc.description.abstractNKG2D (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 α1α2 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.en
dc.description.sponsorshipLeukaemia and Lymphoma Researchen
dc.language.isoenen
dc.publisherAmerican Association for the Advancement of Scienceen
dc.relation.urlhttp://stke.sciencemag.org/content/10/481/eaai8904en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectNKG2Den
dc.subjectULBP6en
dc.subjectPolymorphismen
dc.subjectCell killingen
dc.titleA disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D-ligand bindingen
dc.typeArticleen
dc.identifier.journalScience Signalingen
dc.date.accepted2017-05-
rioxxterms.funderLeukaemia and Lymphoma Researchen
rioxxterms.identifier.projectUoW090617AAen
rioxxterms.versionAMen
rioxxterms.licenseref.urihttps://creativecommons.org/CC BY-NC-ND 4.0en
rioxxterms.licenseref.startdate2017-06-09en
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