Structural Basis for CD96 Immune Receptor Recognition of Nectin-like Protein-5, CD155

Research output: Contribution to journalArticleResearchpeer-review

Abstract

CD96, DNAM-1, and TIGIT constitute a group of immunoglobulin superfamily receptors that are key regulators of tumor immune surveillance. Within this axis, CD96 recognizes the adhesion molecule nectin-like protein-5 (necl-5), although the molecular basis underpinning this interaction remains unclear. We show that the first immunoglobulin domain (D1) of CD96 is sufficient to mediate a robust interaction with necl-5, but not the DNAM-1 and TIGIT ligand, nectin-2. The crystal structure of CD96-D1 bound to the necl-5 ectodomain revealed that CD96 recognized necl-5 D1 via a conserved “lock-and-key” interaction observed across TIGIT:necl complexes. Specific necl-5 recognition was underpinned by a novel structural motif within CD96, namely an “ancillary key”. Mutational analysis showed that this specific residue was critical for necl-5 binding, while simultaneously providing insights into the unique ligand specificity of CD96.
Original languageEnglish
Pages (from-to)219-228
Number of pages10
JournalStructure
Volume27
Issue number2
DOIs
Publication statusPublished - 5 Feb 2019

Keywords

  • immune receptor
  • immune checkpoint
  • nectin adhesion proteins
  • cancer
  • receptor-ligand interaction
  • immune escape
  • tumour recognition

Cite this

@article{30ccb9e7b21f481f9d6cb2235297ea9f,
title = "Structural Basis for CD96 Immune Receptor Recognition of Nectin-like Protein-5, CD155",
abstract = "CD96, DNAM-1, and TIGIT constitute a group of immunoglobulin superfamily receptors that are key regulators of tumor immune surveillance. Within this axis, CD96 recognizes the adhesion molecule nectin-like protein-5 (necl-5), although the molecular basis underpinning this interaction remains unclear. We show that the first immunoglobulin domain (D1) of CD96 is sufficient to mediate a robust interaction with necl-5, but not the DNAM-1 and TIGIT ligand, nectin-2. The crystal structure of CD96-D1 bound to the necl-5 ectodomain revealed that CD96 recognized necl-5 D1 via a conserved “lock-and-key” interaction observed across TIGIT:necl complexes. Specific necl-5 recognition was underpinned by a novel structural motif within CD96, namely an “ancillary key”. Mutational analysis showed that this specific residue was critical for necl-5 binding, while simultaneously providing insights into the unique ligand specificity of CD96.",
keywords = "immune receptor, immune checkpoint, nectin adhesion proteins, cancer, receptor-ligand interaction, immune escape, tumour recognition",
author = "Deuss, {Felix A.} and Watson, {Gabrielle M.} and Zhihui Fu and Jamie Rossjohn and Richard Berry",
year = "2019",
month = "2",
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doi = "10.1016/j.str.2018.10.023",
language = "English",
volume = "27",
pages = "219--228",
journal = "Structure",
issn = "0969-2126",
publisher = "Elsevier",
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Structural Basis for CD96 Immune Receptor Recognition of Nectin-like Protein-5, CD155. / Deuss, Felix A.; Watson, Gabrielle M.; Fu, Zhihui; Rossjohn, Jamie; Berry, Richard.

In: Structure, Vol. 27, No. 2, 05.02.2019, p. 219-228.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural Basis for CD96 Immune Receptor Recognition of Nectin-like Protein-5, CD155

AU - Deuss, Felix A.

AU - Watson, Gabrielle M.

AU - Fu, Zhihui

AU - Rossjohn, Jamie

AU - Berry, Richard

PY - 2019/2/5

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N2 - CD96, DNAM-1, and TIGIT constitute a group of immunoglobulin superfamily receptors that are key regulators of tumor immune surveillance. Within this axis, CD96 recognizes the adhesion molecule nectin-like protein-5 (necl-5), although the molecular basis underpinning this interaction remains unclear. We show that the first immunoglobulin domain (D1) of CD96 is sufficient to mediate a robust interaction with necl-5, but not the DNAM-1 and TIGIT ligand, nectin-2. The crystal structure of CD96-D1 bound to the necl-5 ectodomain revealed that CD96 recognized necl-5 D1 via a conserved “lock-and-key” interaction observed across TIGIT:necl complexes. Specific necl-5 recognition was underpinned by a novel structural motif within CD96, namely an “ancillary key”. Mutational analysis showed that this specific residue was critical for necl-5 binding, while simultaneously providing insights into the unique ligand specificity of CD96.

AB - CD96, DNAM-1, and TIGIT constitute a group of immunoglobulin superfamily receptors that are key regulators of tumor immune surveillance. Within this axis, CD96 recognizes the adhesion molecule nectin-like protein-5 (necl-5), although the molecular basis underpinning this interaction remains unclear. We show that the first immunoglobulin domain (D1) of CD96 is sufficient to mediate a robust interaction with necl-5, but not the DNAM-1 and TIGIT ligand, nectin-2. The crystal structure of CD96-D1 bound to the necl-5 ectodomain revealed that CD96 recognized necl-5 D1 via a conserved “lock-and-key” interaction observed across TIGIT:necl complexes. Specific necl-5 recognition was underpinned by a novel structural motif within CD96, namely an “ancillary key”. Mutational analysis showed that this specific residue was critical for necl-5 binding, while simultaneously providing insights into the unique ligand specificity of CD96.

KW - immune receptor

KW - immune checkpoint

KW - nectin adhesion proteins

KW - cancer

KW - receptor-ligand interaction

KW - immune escape

KW - tumour recognition

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