Thermodynamic Analysis of Degenerate Recognition by the NKG2D Immunoreceptor

McFarland, Benjamin J.; Strong, Roland K.

doi:10.1016/s1074-7613(03)00320-0

Cited by 90 publications

(83 citation statements)

References 51 publications

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“…Two tyrosine residues of NKG2D make important contacts at each of the NKG2D monomer interfaces with MIC-A and ULBP3, but recognize an almost completely different set of amino acids on their interaction partners. Nevertheless, the conformation of the NKG2D binding surface is similar between these two structures [26].…”

Section: Receptor Binding Of Multiple Distinct Ligands Without Substamentioning

confidence: 84%

Polyspecificity of T cell and B cell receptor recognition

Wucherpfennig

Allen

Celada

et al. 2007

Seminars in Immunology

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197

171

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A recent workshop discussed the recognition of multiple distinct ligands by individual T cell and B cell receptors and the implications of this discovery for lymphocyte biology. The workshop recommends general use of the term polyspecificity because it emphasizes two fundamental aspects, the inherent specificity of receptor recognition and the ability to recognize multiple ligands. Many different examples of polyspecificity and the structural mechanisms were discussed, and the group concluded that polyspecificity is a general, inherent feature of TCR and antibody recognition. This review summarizes the relevance of polyspecificity for lymphocyte development, activation and disease processes.

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Section: Receptor Binding Of Multiple Distinct Ligands Without Substamentioning

confidence: 84%

Polyspecificity of T cell and B cell receptor recognition

Wucherpfennig

Allen

Celada

et al. 2007

Seminars in Immunology

Self Cite

197

171

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“…Detailed analysis of NKG2D interactions with its ligands of several different families has led to the conclusion that NKG2D interacts via rigid adaptation (35,37), a mechanism whereby the initial interaction is via a "lock and key" mechanism, but for some ligands the stabilization of the interaction requires conformational adjustment of residues at the periphery of the interaction site. For the m152/RAE1 cis interaction, in the absence of a structure of unliganded m152 or RAE1γ, we cannot determine whether there is significant molecular adjustment of the m152.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Wang¹,

Natarajan²,

Revilleza³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells are activated by engagement of the NKG2D receptor with ligands on target cells stressed by infection or tumorigenesis. Several human and rodent cytomegalovirus (CMV) immunoevasins down-regulate surface expression of NKG2D ligands. The mouse CMV MHC class I (MHC-I)-like m152/gp40 glycoprotein down-regulates retinoic acid early inducible-1 (RAE1) NKG2D ligands as well as host MHC-I. Here we describe the crystal structure of an m152/RAE1γ complex and confirm the intermolecular contacts by mutagenesis. m152 interacts in a pincer-like manner with two sites on the α1 and α2 helices of RAE1 reminiscent of the NKG2D interaction with RAE1. This structure of an MHC-I-like immunoevasin/MHC-I-like ligand complex explains the binding specificity of m152 for RAE1 and allows modeling of the interaction of m152 with classical MHC-I and of related viral immunoevasins.immune recognition | virus evasion | X-ray diffraction C ytomegaloviruses (CMV), members of the β-herpesvirus family, pathogenic in immunosuppressed or immunodeficient hosts (1), may lie dormant for many years but can cause considerable morbidity and mortality with neonatal or HIV infection or during organ transplantation (2). The large size of the CMV dsDNA genomes (as large as 250 kb), allows these viruses to dedicate many genes to viral fitness; a number of these genes thwart the host inflammatory, innate, and adaptive immune responses. Human and mouse studies emphasize the importance of natural killer (NK) and CD8 + T cells in the antiviral response, underscoring the complementary roles of innate and adaptive immunity. Of particular importance to NK-mediated immunity is NKG2D, a C-type lectin-like homodimeric glycoprotein that mediates NK cell activation on ligation by host molecules expressed at the cell surface as a result of cellular or genotoxic stress (3, 4). Human NKG2D ligands include MICA, MICB, and members of the ULBP family (4, 5), and studies suggest a complex relationship between the expression of NKG2D ligands on tumor cells, the effectiveness of immunosurveillance, and clinical prognosis (6, 7). Murine NKG2D recognizes RAE1 family members (RAE1α-ε), H60 (H60a-c), and the murine UL16-binding protein-like transcript 1 (MULT1) (8-10). Remarkably, these NKG2D ligands are related to MHC class I (MHC-I)-like molecules (11,12), and several are targets of MHC-I-like immunoevasins (3). In particular, mouse CMV (MCMV) m152/gp40 (hereafter referred to as "m152") has a dual role, downregulating cell-surface expression of RAE1 family members [but not MULT1 or H60 (13), the targets of MCMV proteins m145 and m155, respectively (14, 15)] as well as host MHC-I molecules (16)(17)(18)(19). A virus-encoded Fc receptor, m138, also controls MULT1, H60 (3), and RAE1ε (20). In vivo, MCMV deletions lacking m145, m152, m155, or m138 are defective in viral control of surface expression of MULT1, RAE1, and H60.To explore the mechanism by which MCMV MHC-I-like immunoevasins interact with and down-regulate their respective NKG2D ligands, we examined th...

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“…Alternatively, the Ag combining site of 2D10, isolated during a secondary immune response representing an in vivo scenario, embodies two distinct binding motifs within the same conformation. Recognition of distinct ligands without any induced fit but through rigid protein-protein interactions has been observed in case of T cell epitope receptor interactions as well (54)(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Structural Evaluation of a Mimicry-Recognizing Paratope: Plasticity in Antigen–Antibody Interactions Manifests in Molecular Mimicry

Tapryal

Gaur

Kaur

et al. 2013

The Journal of Immunology

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Molecular mimicry manifests antagonistically with respect to the specificity of immune recognition. However, it often occurs because different Ags share surface topologies in terms of shape or chemical nature. It also occurs when a flexible paratope accommodates dissimilar Ags by adjusting structural features according to the antigenic epitopes or differential positioning in the Ag combining site. Toward deciphering the structural basis of molecular mimicry, mAb 2D10 was isolated from a maturing immune response elicited against methyl α-d-mannopyranoside and also bound equivalently to a dodecapeptide. The physicochemical evidence of this carbohydrate–peptide mimicry in the case of mAb 2D10 had been established earlier. These studies had strongly suggested direct involvement of a flexible paratope in the observed mimicry. Surprisingly, comparison of the Ag-free structure of single-chain variable fragment 2D10 with those bound to sugar and peptide Ags revealed a conformationally invariant state of the Ab while binding to chemically and structurally disparate Ags. This equivalent binding of the two dissimilar Ags was through mutually independent interactions, demonstrating functional equivalence in the absence of structural correlation. Thus, existence of a multispecific, mature Ab in the secondary immune response was evident, as was the plasticity in the interactions while accommodating topologically diverse Ags. Although our data highlight the structural basis of receptor multispecificity, they also illustrate mechanisms adopted by the immune system to neutralize the escape mutants generated during pathogenic insult.

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Thermodynamic Analysis of Degenerate Recognition by the NKG2D Immunoreceptor

Cited by 90 publications

References 51 publications

Polyspecificity of T cell and B cell receptor recognition

Polyspecificity of T cell and B cell receptor recognition

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Structural Evaluation of a Mimicry-Recognizing Paratope: Plasticity in Antigen–Antibody Interactions Manifests in Molecular Mimicry

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