{"doi":"10.1016/j.jbc.2025.110665","title":"A biophysical and molecular characterization of the interaction between the Alzheimer risk factor BIN1 and the neuronal scaffold protein p140Cap","abstract":"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.","journal":"Journal of Biological Chemistry","year":2025,"id":573786,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":428851,"name":"Eric M. Lewandowski","orcid":"0000-0001-6235-6502","position":1,"is_corresponding":false},{"id":830561,"name":"Natasha Ram","orcid":null,"position":2,"is_corresponding":false},{"id":107692,"name":"Xiujun Zhang","orcid":"0000-0001-8041-0592","position":3,"is_corresponding":false},{"id":847987,"name":"Shuai Wang","orcid":"0000-0002-9252-7496","position":4,"is_corresponding":false},{"id":1459291,"name":"Om Patel","orcid":null,"position":5,"is_corresponding":false},{"id":299455,"name":"Lisa Collier","orcid":"0000-0002-3861-0125","position":6,"is_corresponding":false},{"id":1480943,"name":"Paola Defilippi","orcid":"0000-0001-6427-4906","position":7,"is_corresponding":false},{"id":1149062,"name":"Yu Chen","orcid":"0000-0002-8206-3325","position":8,"is_corresponding":false},{"id":271836,"name":"Gopal Thinakaran","orcid":"0000-0001-5523-6780","position":9,"is_corresponding":false},{"id":661374,"name":"Danielle M. Blazier","orcid":"0000-0001-9935-2660","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T02:57:36.753600Z","pmid":"40889683","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}