Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site

Joyce, Michael; Tran, Paul; Zhuravleva, Marina A.; Jaw, Jessica; Colonna, Marco; Sun, Peter D.

doi:10.1073/pnas.1100622108

Cited by 60 publications

(78 citation statements)

References 45 publications

(48 reference statements)

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“…2 and Table 1). Interestingly, differential alterations in ligand binding affinity (direct receptor-ligand interaction) and avidity (local increase of ligand binding sites due to receptor oligomerization) of the NKp30 stalk mutants were found for the two cellular ligands BAG-6 and B7-H6, although the crystal structures of NKp30 (PDB code 3NOI) and NKp30 ligated to B7-H6 (PDB code 3PV6) imply ligand binding at the Ig domain of NKp30 (36,37). This might be explained by differences in methodology and binding sites of B7-H6 and BAG-6 within NKp30 (26).…”

Section: Discussionmentioning

confidence: 99%

The Stalk Domain of NKp30 Contributes to Ligand Binding and Signaling of a Preassembled NKp30-CD3ζ Complex

Memmer

Weil

Beyer

et al. 2016

Journal of Biological Chemistry

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Edited by Peter CresswellThe natural cytotoxicity receptor (NCR) NKp30 (CD337) is a key player for NK cell immunosurveillance of infections and cancer. The molecular details of ligand recognition and its connection to CD3 signaling remain unsolved. Here, we show that the stalk domain ( 129 KEHPQLGAGTVLLLR 143 ) of NKp30 is very sensitive to sequence alterations, as mutations lead to impaired ligand binding and/or signaling capacity. Surprisingly, the stalk domains of NKp30 and NKp46, another NCR employing CD3 for signaling, were not exchangeable without drastic deficiencies in folding, plasma membrane targeting, and/or ligand-induced receptor signaling. Further mutational studies, N-glycosylation mapping, and plasma membrane targeting studies in the absence and presence of CD3 suggest two interconvertible types of NCR-CD3 assemblies: 1) a signaling incompetent structural NKp30-CD3 complex and 2) a ligandinduced signaling competent NKp30-CD3 complex. Moreover, we propose that ligand binding triggers translocation of Arg-143 from the membrane interface into the membrane to enable alignment with oppositely charged aspartate residues within CD3 and activation of CD3-signaling.

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Section: Discussionmentioning

confidence: 99%

The Stalk Domain of NKp30 Contributes to Ligand Binding and Signaling of a Preassembled NKp30-CD3ζ Complex

Memmer

Weil

Beyer

et al. 2016

Journal of Biological Chemistry

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“…12,13,[17][18][19][20][21] Thus far, the expression of B7-H6 has been shown to be restricted to tumor cells and absent from normal hematopoietic cells from healthy individuals at steady state. 12,17 It is well known that B7 family members are induced on myeloid cells upon stimulation with infectious and proinflammatory stimuli.…”

Section: Discussionmentioning

confidence: 99%

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Matta

Baratin

Chiche

et al. 2013

Blood

119

128

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• B7-H6 transcripts, B7-H6 cell-surface expression, and sB7-H6 can be induced in inflammatory conditions in vitro and in vivo.• B7-H6 is expressed on proinflammatory CD141 CD16 1 monocytes in sepsis conditions and is linked to an increased mortality.B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14 1 CD16 1 proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll-like receptors or proinflammatory cytokines such as interleukin-1b and tumor necrosis factor a. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14 1 CD16 1 monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions. This trial was registered at www.clinicaltrials.gov as #NTC00699868. (Blood. 2013;122(3):394-404)

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“…NKp30 consists of a single IgV domain in its extracellular region, a unique structural feature of the CD28 family (22). Another ligand of NKp30 is HLA-B associated transcript, which is a nuclear protein involved in the tumor protein p53 signaling pathway and apoptosis induction following DNA damage-induced cellular stress (23,24).…”

Section: Percentage Of Patients -------------------------------------mentioning

confidence: 99%

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

Sun

Hong

et al. 2017

Oncology Letters

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Abstract. B7 homolog 6 (B7-H6), a member of the B7 family, is as a cell-surface ligand for natural cytotoxicity triggering receptor 3, which is expressed on natural killer cells. It has previously been reported that B7-H6 is undetectable in normal human tissues but is expressed on tumor cells. However, there are few studies focusing on the clinical significance of B7-H6 expression in human carcinoma, with the exception of three studies on ovarian, lung and gastric cancer. The present study investigated the expression of B7-H6 protein in pathologic tissue samples from 305 patients with breast cancer using immunohistochemistry. A high B7-H6 expression level was identified in tissues from 32.13% of patients with breast cancer. These patients were revealed to also exhibit a high expression level of human epidermal growth factor receptor 2, a shorter survival time and a higher rate of lymph node metastasis. Furthermore, the expression level of B7-H6 was not associated with patient age, breast cancer subtype, tumor size, tumor location or estrogen receptor expression. The results of the present study revealed that higher B7-H6 expression level in breast cancer tissues was positively associated with tumor progression. This indicates that B7-H6 is associated with the progression and immunoevasion of human breast cancer; however, the molecular mechanisms underlying this potential effect require further investigation. IntroductionB7 homolog 6 (B7-H6), a novel member of the B7 family, was identified on tumor cell surfaces in 2009 (1). B7-H6 has sequence homology with other B7 molecules and similar to other members of the B7 family, B7-H6 contains two extracellular immunoglobulin (Ig) domains; however, the receptor for B7-H6, located on natural killer (NK) cells, was not consistent with other B7 family member receptors, which are located on activated T cells. The receptor for B7-H6 is natural cytotoxicity triggering receptor 3 (NKp30) (1-3). NK cells are large granular lymphocytes that produce chemokines and cytokines, and participate in the inflammatory and adaptive immune response (4). NK cells are also an important part of the innate immune system as they directly kill transformed and virally infected cells (5).B7 family members serve an essential role in regulating the immune response against transformed cells through a variety of mechanisms (6). As specific niches of B7 family members continue to be dissected, their diagnostic and therapeutic potential in tumors is becoming more apparent (6,7), and this was highlighted in 2011 by the US Food and Drug Administration approval of an antibody targeting programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 in cancer (8,9). The ability to successfully target cell cycle checkpoint regulators has since led to multiple clinical trials investigating antibodies targeting the signaling pathway that the B7 family participate in (10).B7-H6 binds to NKp30, triggering antitumor NK cell cytotoxicity and cytokine secretion, thus B7-H6 functions as a tumor-ind...

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Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site

Cited by 60 publications

References 45 publications

The Stalk Domain of NKp30 Contributes to Ligand Binding and Signaling of a Preassembled NKp30-CD3ζ Complex

The Stalk Domain of NKp30 Contributes to Ligand Binding and Signaling of a Preassembled NKp30-CD3ζ Complex

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer

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