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A biophysical and molecular characterization of the interaction between the Alzheimer risk factor BIN1 and the neuronal scaffold protein p140Cap
Danielle M. Blazier, Eric M. Lewandowski, Natasha Ram, Xiujun Zhang, Shuai Wang, Om Patel, Lisa A. Collier, Paola Defilippi et al.. Journal of Biological Chemistry, 2025-08-30
Topic: Brain proteins, microglia and lab models
Bridging Integrator 1 (BIN1) is a genetic risk factor for late-onset Alzheimer disease. BIN1's participation in endocytosis, membrane remodeling, and modulation of actin dynamics is well-characterized in non-neuronal cells. In neurons, BIN1 is enriched at presynaptic sites, where it facilitates excitatory neurotransmitter vesicle release. However, how BIN1 is involved in synaptic vesicle dynamics is not well understood. A C-terminal Src Homology 3 (SH3) domain is invariant in all BIN1 isoforms and promotes protein-protein interactions with proteins harboring proline-rich motifs. While BIN1 interactions with dynamin, synaptojanin, RIN3, and tau have been identified and experimentally validated, the list of BIN1-interacting molecules is not exhaustive. Here, we report the neuronal scaffolding protein p140Cap, encoded by SRCIN1 , as a BIN1 SH3 domain-interacting protein. We performed surface plasmon resonance to ascertain the affinity of BIN1-SH3 domain for p140Cap and identified a peptide containing three proline-rich motifs that exhibited biologically relevant affinity (K D = 7.7 μM). Additional surface plasmon resonance experiments, coupled with alanine-scanning mutagenesis, revealed that two class II motifs, but not a class I motif, in p140Cap facilitated binding. Confocal microscopy and proximity ligation assays confirmed that BIN1 colocalizes with, and is within molecular distance of, p140Cap in cultured cells and in the mouse brain. Co-immunoprecipitation assays validated the interaction, and glutathione S-transferase pull-down revealed that a rare BIN1 coding variant ( rs138047593 ) significantly reduces p140Cap and tau binding, highlighting the impact of this mutant on interacting protein binding efficiency. The functional implications of BIN1:p140Cap interaction for neuronal functions warrant further investigation.
Key findings
- Additional surface plasmon resonance experiments, coupled with alanine-scanning mutagenesis, revealed that two class II motifs, but not a class I motif, in p140Cap facilitated binding.
- Co-immunoprecipitation assays validated the interaction, and glutathione S-transferase pull-down revealed that a rare BIN1 coding variant ( rs138047593 ) significantly reduces p140Cap and tau binding, highlighting the impact of this mutant on interacting protein binding efficiency.
Why it matters
This biophysical study identified the neuronal scaffold protein p140Cap as a BIN1 SH3 domain-interacting protein and found that a rare BIN1 coding variant significantly reduces p140Cap and tau binding. The work characterizes a molecular interaction related to a late-onset Alzheimer's risk gene, but it does not test any treatment, cure or prevention.
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Study details
- Evidence strengthLow
How this study scored 35/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Biological Chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 0 / 6 | Cited 0.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Gopal Thinakaran: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Turin: institution h-index 903 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40889683) |
| Free to read | 2 / 2 | Free to read |
| Total | 35 / 100 | — |
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Read the original
- DOI: 10.1016/j.jbc.2025.110665
- PubMed: 40889683
- Original source →
- Free full text: Journal of Biological Chemistry →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Blazier, D. M., Lewandowski, E. M., Ram, N., Zhang, X., Wang, S., Patel, O., et al. (2025). A biophysical and molecular characterization of the interaction between the Alzheimer risk factor BIN1 and the neuronal scaffold protein p140Cap. Journal of Biological Chemistry. https://doi.org/10.1016/j.jbc.2025.110665
Vancouver
Blazier DM, Lewandowski EM, Ram N, Zhang X, Wang S, Patel O, et al. A biophysical and molecular characterization of the interaction between the Alzheimer risk factor BIN1 and the neuronal scaffold protein p140Cap. Journal of Biological Chemistry. 2025. doi:10.1016/j.jbc.2025.110665. PMID: 40889683.
BibTeX
@article{blazier2025-40889683,
author = {Blazier, Danielle M. and Lewandowski, Eric M. and Ram, Natasha and Zhang, Xiujun and Wang, Shuai and Patel, Om and Collier, Lisa A. and Defilippi, Paola and others},
title = {{A biophysical and molecular characterization of the interaction between the Alzheimer risk factor BIN1 and the neuronal scaffold protein p140Cap}},
journal = {Journal of Biological Chemistry},
year = {2025},
doi = {10.1016/j.jbc.2025.110665},
pmid = {40889683},
url = {https://doi.org/10.1016/j.jbc.2025.110665}
}
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