Human immunomodulatory ligand B7-1 mediates synaptic remodeling via the p75 neurotrophin receptor
Nicholas C. Morano, … , Barbara L. Hempstead, Steven C. Almo
Nicholas C. Morano, … , Barbara L. Hempstead, Steven C. Almo
Published September 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e157002. https://doi.org/10.1172/JCI157002.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 3

Human immunomodulatory ligand B7-1 mediates synaptic remodeling via the p75 neurotrophin receptor

Abstract

Cell surface receptors, ligands, and adhesion molecules underlie development, circuit formation, and synaptic function of the central nervous system and represent important therapeutic targets for many neuropathologies. The functional contributions of interactions between cell surface proteins of neurons and nonneuronal cells have not been fully addressed. Using an unbiased protein-protein interaction screen, we showed that the human immunomodulatory ligand B7-1 (hB7-1) interacts with the p75 neurotrophin receptor (p75NTR) and that the B7-1:p75NTR interaction is a recent evolutionary adaptation present in humans and other primates, but absent in mice, rats, and other lower mammals. The surface of hB7-1 that engages p75NTR overlaps with the hB7-1 surface involved in CTLA-4/CD28 recognition, and these molecules directly compete for binding to p75NTR. Soluble or membrane-bound hB7-1 altered dendritic morphology of cultured hippocampal neurons, with loss of the postsynaptic protein PSD95 in a p75NTR-dependent manner. Abatacept, an FDA-approved therapeutic (CTLA-4–hFc fusion) inhibited these processes. In vivo injection of hB7-1 into the murine subiculum, a hippocampal region affected in Alzheimer’s disease, resulted in p75NTR-dependent pruning of dendritic spines. Here, we report the biochemical interaction between B7-1 and p75NTR, describe biological effects on neuronal morphology, and identify a therapeutic opportunity for treatment of neuroinflammatory diseases.

Authors

Nicholas C. Morano, Roshelle S. Smith, Victor Danelon, Ryan Schreiner, Uttsav Patel, Natalia G. Herrera, Carla Smith, Steven M. Olson, Michelle K. Laerke, Alev Celikgil, Scott J. Garforth, Sarah C. Garrett-Thomson, Francis S. Lee, Barbara L. Hempstead, Steven C. Almo

×

Figure 3

Identification of the binding interface of hB7-1 and PTPRF on p75NTR using epitope- mapping and ligand-competition experiments.

Options: View larger image (or click on image) Download as PowerPoint
Identification of the binding interface of hB7-1 and PTPRF on p75NTR usi...
(A) p75NTR residues identified as important for hB7-1 binding mapped onto crystal structure of rat p75NTR bound to NT3 (PDB: 3BUK) affect binding to B7-1 (red), make contacts with NT3 and also affect binding to B7-1 (brown), and make H bond contacts with NT3 (blue). (B) The hB7-1–binding site modeled onto the dimeric structure of p75NTR bound to an NT3 dimer (PDB: 3BUK). (C) Ligand-competition experiments showing that NGF and hB7-1 compete for binding to p75NTR at high concentrations. n = 3. (D) Cells expressing p75NTR -F136K and F136H demonstrate binding to B7-1N82E–expressing cells as well as WT B7-1–expressing cells. ****P < 0.0001, 1-way ANOVA with multiple comparisons. n = 4. (E) Crystal structures of hB7-1 and p75NTR indicating proposed interaction between p75NTR-F136 and B7-1–N82. Each assay represents the indicated number of independent experiments, which each include a single replicate. Error bars represent SEM.