Cutting Edge: Class II–like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

Kuroki, Kazuhiko; Mio, Kazuhiro; Takahashi, Ami; Matsubara, Haruki; Kasai, Yoshiyuki; Manaka, Sachie; Kikkawa, Masahide; Hamada, Daizo; Sato, Chikara; Maenaka, Katsumi

doi:10.4049/jimmunol.1601296

Cited by 18 publications

(22 citation statements)

References 13 publications

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“…For instance, the intronic tails of both protomers could interact with each other, not causing the effect of cleft deformation observed in our simulations (Supplementary Material -HLA-G5 Monomer and nonapeptide Simulation Video). Such dimeric structures for HLA-G5 without b2microglobulin could be similar to the dimers composed by the a1-a3: a1-a3 domains, as in the work published by Kuroki et al, in which HLA-G2 isoform (membrane bound a1-a3) naturally formed a b2-microglobulin-free homodimer which did not have disulfide bridges keeping the structures in place (77). Electron microscopy revealed that the general structure and domain organization of such HLA-G2 homodimers resembled those of class II HLA heterodimers (a1-a2: b1-b2) (20).…”

Section: Discussionsupporting

confidence: 54%

“…Electron microscopy revealed that the general structure and domain organization of such HLA-G2 homodimers resembled those of class II HLA heterodimers (a1-a2: b1-b2) (20). Published data (77) described the binding of b2-microglobulin and b2-microglobulin-free forms of HLA molecules to members of ILT receptor family and demonstrated that, in addition to ILT4, b2microglobulin-free structures are recognized by several other members of this receptor family. In fact, the "activating" members of the ILT family showed a preference for such structures.…”

Section: Discussionmentioning

confidence: 98%

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Structural Modeling and Molecular Dynamics of the Immune Checkpoint Molecule HLA-G

et al. 2020

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HLA-G is considered to be an immune checkpoint molecule, a function that is closely linked to the structure and dynamics of the different HLA-G isoforms. Unfortunately, little is known about the structure and dynamics of these isoforms. For instance, there are only seven crystal structures of HLA-G molecules, being all related to a single isoform, and in some cases lacking important residues associated to the interaction with leukocyte receptors. In addition, they lack information on the dynamics of both membrane-bound HLA-G forms, and soluble forms. We took advantage of in silico strategies to disclose the dynamic behavior of selected HLA-G forms, including the membrane-bound HLA-G1 molecule, soluble HLA-G1 dimer, and HLA-G5 isoform. Both the membrane-bound HLA-G1 molecule and the soluble HLA-G1 dimer were quite stable. Residues involved in the interaction with ILT2 and ILT4 receptors (a3 domain) were very close to the lipid bilayer in the complete HLA-G1 molecule, which might limit accessibility. On the other hand, these residues can be completely exposed in the soluble HLA-G1 dimer, due to the free rotation of the disulfide bridge (Cys42/Cys42). In fact, we speculate that this free rotation of each protomer (i.e., the chains composing the dimer) could enable alternative binding modes for ILT2/ILT4 receptors, which in turn could be associated with greater affinity of the soluble HLA-G1 dimer. Structural analysis of the HLA-G5 isoform demonstrated higher stability for the complex containing the peptide and coupled b2-microglobulin, while structures lacking such domains were significantly unstable. This study reports for the first time structural conformations for the HLA-G5 isoform and the dynamic behavior of HLA-G1 molecules under simulated biological conditions. All modeled structures were made available through GitHub (https://github.com/KavrakiLab/), enabling their use as templates for modeling other alleles and isoforms, as well as for other computational analyses to investigate key molecular interactions.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 98%

Structural Modeling and Molecular Dynamics of the Immune Checkpoint Molecule HLA-G

et al. 2020

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“…The Cys147-Cys147 homodimers that might be formed in the a1-deleted a2a3 molecules would possess two receptor binding sites which may affect the specificity or modulate the affinity of such HLA-G isoforms for their receptors. Recently, the group of Maenaka reported that HLA-G2, which lacks the a2 domain, naturally forms a b2microglobulin-free and nondisulfide-linked homodimer having an overall structure that resembles that of the HLA class II heterodimer (Kuroki et al, 2017). These homodimers were shown to bind the LILRB/ILT receptors with slow dissociation and a significant avidity effect.…”

Section: Discussionmentioning

confidence: 99%

Novel landscape of HLA‐G isoforms expressed in clear cell renal cell carcinoma patients

et al. 2017

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Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA‐G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor‐infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in‐depth the HLA‐G isoforms expressed in these tumors. We found that the expression of HLA‐G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter‐ and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA‐G isoforms which includes spliced forms that have an extended 5′‐region and lack the transmembrane and alpha‐1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA‐G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications.

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“…HLA-G2 also has a membrane-anchoring form and contains only two domains, α1 and α3, with a heavy chain in the extracellular region. Our recent biochemical and electron microscopic studies revealed that the ectodomain of HLA-G2 forms a homodimer via non-covalent interactions and strongly binds to LILRB2 [9,17]. Furthermore, HLA-G2 is considered to play an important role in humans who cannot produce functional HLA-G1 due to an HLA-G–null allele [18,19].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms

Furukawa

Meguro

Yamazaki

et al. 2019

IJMS

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The human leucocyte antigen (HLA)-G, which consists of seven splice variants, is a tolerogenic immune checkpoint molecule. It plays an important role in the protection of the fetus from the maternal immune response by binding to inhibitory receptors, including leukocyte Ig-like receptors (LILRs). Recent studies have also revealed that HLA-G is involved in the progression of cancer cells and the protection from autoimmune diseases. In contrast to its well characterized isoform, HLA-G1, the binding activities of other major HLA-G isoforms, such as HLA-G2, toward available anti-HLA-G antibodies are only partially understood. Here, we investigate the binding specificities of anti-HLA-G antibodies by using surface plasmon resonance. MEM-G9 and G233 showed strong affinities to HLA-G1, with a nM range for their dissociation constants, but did not show affinities to HLA-G2. The disulfide-linker HLA-G1 dimer further exhibited significant avidity effects. On the other hand, 4H84 and MEM-G1, which can be used for the Western blotting of HLA-G isoforms, can bind to native HLA-G2, while MEM-G9 and G233 cannot. These results reveal that HLA-G2 has a partially intrinsically disordered structure. Furthermore, MEM-G1, but not 4H84, competes with the LILRB2 binding of HLA-G2. These results provide novel insight into the functional characterization of HLA-G isoforms and their detection systems.

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Cutting Edge: Class II–like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

Cited by 18 publications

References 13 publications

Structural Modeling and Molecular Dynamics of the Immune Checkpoint Molecule HLA-G

Structural Modeling and Molecular Dynamics of the Immune Checkpoint Molecule HLA-G

Novel landscape of HLA‐G isoforms expressed in clear cell renal cell carcinoma patients

Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms

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