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

Structure. 2019 Feb 5;27(2):219-228.e3. doi: 10.1016/j.str.2018.10.023. Epub 2018 Dec 6.


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: cancer; immune checkpoint; immune escape; immune receptor; nectin adhesion proteins; receptor-ligand interaction; tumour recognition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / chemistry*
  • Antigens, CD / metabolism*
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Domains
  • Protein Structure, Secondary
  • Receptors, Virus / chemistry*
  • Receptors, Virus / metabolism*
  • Sf9 Cells


  • Antigens, CD
  • CD96 antigen
  • Receptors, Virus
  • poliovirus receptor