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.
| Original language | English |
|---|---|
| Pages (from-to) | 12534-12546 |
| Number of pages | 13 |
| Journal | Journal of Biological Chemistry |
| Volume | 294 |
| Issue number | 33 |
| DOIs | |
| Publication status | Published - 16 Aug 2019 |
Keywords
- DNAX accessory molecule-1 (DNAM-1)
- cancer immunotherapy
- CD226 molecule
- nectin-like protein-5 (NECL-5)
- PVR cell adhesion molecule
- protein structure
- immunology
- immunoglobulin fold
- cell adhesion
- natural killer cells (NK cells)
Cite this
}
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 journal › Article › Research › peer-review
TY - JOUR
T1 - Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1
AU - Deuss, Felix A
AU - Watson, Gabrielle M
AU - Goodall, Katharine J
AU - Leece, Isobel
AU - Chatterjee, Sayantani
AU - Fu, Zhihui
AU - Thaysen-Andersen, Morten
AU - Andrews, Daniel M
AU - Rossjohn, Jamie
AU - Berry, Richard
PY - 2019/8/16
Y1 - 2019/8/16
N2 - 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.
AB - 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.
KW - DNAX accessory molecule-1 (DNAM-1)
KW - cancer immunotherapy
KW - CD226 molecule
KW - nectin-like protein-5 (NECL-5)
KW - PVR cell adhesion molecule
KW - protein structure
KW - immunology
KW - immunoglobulin fold
KW - cell adhesion
KW - natural killer cells (NK cells)
UR - http://www.scopus.com/inward/record.url?scp=85070741035&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA119.009261
DO - 10.1074/jbc.RA119.009261
M3 - Article
VL - 294
SP - 12534
EP - 12546
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 1083-351X
IS - 33
ER -