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Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA)

View ORCID ProfileNishant Mehta, Sainiteesh Maddineni, Irimpan I. Mathews, Andres Parra Sperberg, Po-Ssu Huang, Jennifer R. Cochran
doi: https://doi.org/10.1101/597716
Nishant Mehta
1Department of Bioengineering, Stanford University, Stanford, CA 94305
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Sainiteesh Maddineni
1Department of Bioengineering, Stanford University, Stanford, CA 94305
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Irimpan I. Mathews
2Stanford Synchrotron Radiation Laboratory, 2575 Sand Hill Road, Menlo Park, CA 94025
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Andres Parra Sperberg
1Department of Bioengineering, Stanford University, Stanford, CA 94305
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Po-Ssu Huang
1Department of Bioengineering, Stanford University, Stanford, CA 94305
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  • For correspondence: cochran1@stanford.edu possu@stanford.edu
Jennifer R. Cochran
1Department of Bioengineering, Stanford University, Stanford, CA 94305
3Department of Chemical Engineering, Stanford University, Stanford, CA 94305
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  • For correspondence: cochran1@stanford.edu possu@stanford.edu
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Abstract

V-domain Ig Suppressor of T cell Activation (VISTA) is an immune checkpoint protein that inhibits the T - cell response against cancer. Similar to PD-1 and CTLA-4, antibodies that block VISTA signaling can release the brakes of the immune system and promote tumor clearance. VISTA has an Ig-like fold, but little is known about its structure and mechanism of action. Here, we report a 1.85 Å crystal structure of the human VISTA extracellular domain and highlight structural features that make VISTA unique among B7 family members. Through fine-epitope mapping, we also identify solvent-exposed residues that underlie binding to a clinically relevant anti-VISTA antibody. This antibody-binding region is also shown to interact with V-set and Ig domain-containing 3 (VSIG3), the recently proposed functional binding partner of VISTA. The structure and functional epitope determined here will help guide future drug development efforts against this important checkpoint target.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 03, 2019.
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Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA)
Nishant Mehta, Sainiteesh Maddineni, Irimpan I. Mathews, Andres Parra Sperberg, Po-Ssu Huang, Jennifer R. Cochran
bioRxiv 597716; doi: https://doi.org/10.1101/597716
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Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA)
Nishant Mehta, Sainiteesh Maddineni, Irimpan I. Mathews, Andres Parra Sperberg, Po-Ssu Huang, Jennifer R. Cochran
bioRxiv 597716; doi: https://doi.org/10.1101/597716

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