Structural basis for the recognition of nectin-like protein-5 by the human activating immune receptor, DNAM-1

Felix A. Deuss, Gabrielle M. Watson, Katharine J. Goodall, Isobel Leece, Sayantani Chatterjee, Zhihui Fu, Morten Thaysen-Andersen, Daniel M. Andrews, Jamie Rossjohn, Richard Berry

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Nectin and nectin-like (NECL) adhesion molecules are broadly overexpressed in a wide range of cancers. By binding to these adhesion molecules, the immunoreceptors DNAX accessory molecule-1 (DNAM-1), CD96 molecule (CD96), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) play a crucial role in regulating the anticancer activities of immune effector cells. However, within this axis, it remains unclear how DNAM-1 recognizes its cognate ligands. Here, we determined the structure of human DNAM-1 in complex with nectin-like protein-5 (NECL-5) at 2.8 Å resolution. Unexpectedly, we found that the two extracellular domains (D1–D2) of DNAM-1 adopt an unconventional "collapsed" arrangement that is markedly distinct from those in other immunoglobulin-based immunoreceptors. The DNAM-1:NECL-5 interaction was underpinned by conserved lock-and-key motifs located within their respective D1 domains, but also included a distinct interface derived from DNAM-1 D2. Mutation of the signature DNAM-1 "key" motif within the D1 domain attenuated NECL-5 binding and natural killer cell–mediated cytotoxicity. Altogether, our results have implications for understanding the binding mode of an immune receptor family that is emerging as a viable candidate for cancer immunotherapy.
LanguageEnglish
Pages12534-12546
Number of pages13
JournalJournal of Biological Chemistry
Volume294
Issue number33
Early online date28 Jun 2019
DOIs
Publication statusPublished - 16 Aug 2019

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Molecules
Adhesion
T-cells
Cytotoxicity
poliovirus receptor
CD226 antigen
Natural Killer Cells
Immunotherapy
Immunoglobulins
Neoplasms
nectins
Ligands
T-Lymphocytes
Mutation
Proteins
Immunoglobulin Domains

Cite this

Deuss, Felix A. ; Watson, Gabrielle M. ; Goodall, Katharine J. ; Leece, Isobel ; Chatterjee, Sayantani ; Fu, Zhihui ; Thaysen-Andersen, Morten ; Andrews, Daniel M. ; Rossjohn, Jamie ; Berry, Richard. / Structural basis for the recognition of nectin-like protein-5 by the human activating immune receptor, DNAM-1. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 33. pp. 12534-12546.
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abstract = "Nectin and nectin-like (NECL) adhesion molecules are broadly overexpressed in a wide range of cancers. By binding to these adhesion molecules, the immunoreceptors DNAX accessory molecule-1 (DNAM-1), CD96 molecule (CD96), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) play a crucial role in regulating the anticancer activities of immune effector cells. However, within this axis, it remains unclear how DNAM-1 recognizes its cognate ligands. Here, we determined the structure of human DNAM-1 in complex with nectin-like protein-5 (NECL-5) at 2.8 {\AA} resolution. Unexpectedly, we found that the two extracellular domains (D1–D2) of DNAM-1 adopt an unconventional {"}collapsed{"} arrangement that is markedly distinct from those in other immunoglobulin-based immunoreceptors. The DNAM-1:NECL-5 interaction was underpinned by conserved lock-and-key motifs located within their respective D1 domains, but also included a distinct interface derived from DNAM-1 D2. Mutation of the signature DNAM-1 {"}key{"} motif within the D1 domain attenuated NECL-5 binding and natural killer cell–mediated cytotoxicity. Altogether, our results have implications for understanding the binding mode of an immune receptor family that is emerging as a viable candidate for cancer immunotherapy.",
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Structural basis for the recognition of nectin-like protein-5 by the human activating immune receptor, DNAM-1. / Deuss, Felix A.; Watson, Gabrielle M.; Goodall, Katharine J.; Leece, Isobel; Chatterjee, Sayantani; Fu, Zhihui; Thaysen-Andersen, Morten; Andrews, Daniel M.; Rossjohn, Jamie; Berry, Richard.

In: Journal of Biological Chemistry, Vol. 294, No. 33, 16.08.2019, p. 12534-12546.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Deuss, Felix A.

AU - Watson, Gabrielle M.

AU - Goodall, Katharine J.

AU - Leece, Isobel

AU - Chatterjee, Sayantani

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