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The Sequence Basis for Selectivity of Ephrin-B2 for Eph Receptors and Pathogenic Henipavirus G Glycoproteins [EFNB2-D62Q DEEP MUTAGENESIS]

ABSTRACT: Ephrin-B2 (EFNB2) is a ligand for six Eph receptors in humans and also functions as a cell entry receptor for several henipaviruses, which are zoonotic viruses with pandemic potential. Two such viruses, Nipah (NiV) and Hendra (HeV), are highly pathogenic in humans yet do not have any widely approved virus-specific therapeutics or vaccines. Soluble Fc-fusions of EFNB2 (sEFNB2-Fc) are known to bind the attachment glycoprotein G of both viruses and inhibit viral infection of cells. However, the potential of sEFNB2-Fc as a neutralizing agent in vivo is hindered by its binding activity to native Eph receptors. Therefore, using deep mutagenesis, variants of EFNB2 at cell surface are identified with increased binding to the soluble head domain of NiV-G over soluble Fc-fusions of the extracellular domains of Eph receptors. Specificity mutations for NiV-G are found primarily at the binding interface, especially around the G-H binding loop. The mutational landscape offers a preliminary blueprint for engineering sEFNB2-Fc variants with high specificity and affinity for potent neutralization of henipaviruses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234214 | GEO | 2023/06/12

REPOSITORIES: GEO

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The Sequence Basis for Selectivity of Ephrin-B2 for Eph Receptors and Pathogenic Henipavirus G Glycoproteins [EFNB2 DEEP MUTAGENESIS]

Project description:Ephrin-B2 (EFNB2) is a ligand for six Eph receptors in humans and also functions as a cell entry receptor for several henipaviruses, which are zoonotic viruses with pandemic potential. Two such viruses, Nipah (NiV) and Hendra (HeV), are highly pathogenic in humans yet do not have any widely approved virus-specific therapeutics or vaccines. Soluble Fc-fusions of EFNB2 (sEFNB2-Fc) are known to bind the attachment glycoprotein G of both viruses and inhibit viral infection of cells. However, the potential of sEFNB2-Fc as a neutralizing agent in vivo is hindered by its binding activity to native Eph receptors. Therefore, using deep mutagenesis, variants of EFNB2 at cell surface are identified with increased binding to the soluble head domain of NiV-G over soluble Fc-fusions of the extracellular domains of Eph receptors. Specificity mutations for NiV-G are found primarily at the binding interface, especially around the G-H binding loop. The mutational landscape offers a preliminary blueprint for engineering sEFNB2-Fc variants with high specificity and affinity for potent neutralization of henipaviruses.

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Project description:Both ephrins and their receptors are membrane bound, restricting their interactions to the sites of direct cell-to-cell interfaces. They are widely expressed, often co-expressed and regulate developmental processes, cell adhesion, motility, survival, proliferation, and differentiation. Both tumor suppressor and oncogene activities are ascribed to EFNs and Ephs in various contexts. A major conundrum regarding the EFN/Eph system concerns their large number and functional redundancy, given the promiscuous cross-activation of ligands and receptors and the overlapping intracellular signaling pathways. To address this issue, we treated human epidermal keratinocytes with 5 EFNAs individually and defined the transcriptional responses in the cells. We found that a large set of genes is coregulated by all EFNAs. However, while the responses to EFNA3, EFNA 4 and EFNA 5 are identical, the responses to EFNA1 and EFNA2 are characteristic and distinctive. All EFNAs induce epidermal differentiation markers and suppress cell adhesion genes, especially integrins. Ontological analysis shows that all EFNAs induce cornification and keratin genes, while suppressing wound-healing associated, signaling, receptor and ECM associated genes. Transcriptional targets of AP1 are selectively suppressed by EFNAs. EFNA1 and EFNA2, but not the EFNA3, EFNA4, EFNA5 cluster, regulate the members of the ubiquitin-associated proteolysis genes. EFNA1 specifically induces collagen production. Our results demonstrate that the EFN-Eph interactions in the epidermis, while promiscuous, are not redundant but specific. This suggests that different members of the EFN/Eph system have specific, clearly demarcated functions. Human epidermal keratinocytes are treated with 25 ng/ml EFNA1; EFNA2; EFNA3; EFNA4 or EFNA5 (all as Fc conjugates) for 24h.

2011-01-10 | E-GEOD-26521 | biostudies-arrayexpress

The Sequence Basis for Selectivity of Ephrin-B2 for Eph Receptors and Pathogenic Henipavirus G Glycoproteins [EFNB2 DEEP MUTAGENESIS]

Project description:The Sequence Basis for Selectivity of Ephrin-B2 for Eph Receptors and Pathogenic Henipavirus G Glycoproteins [EFNB2 DEEP MUTAGENESIS]

| PRJNA980552 | ENA

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