{"doi":"10.1101/2023.09.24.559210","title":"PDZ Domains from the Junctional Proteins Afadin and ZO-1 Act as Mechanosensors","abstract":"Intercellular adhesion complexes must withstand mechanical forces to maintain tissue cohesion while also retaining the capacity for dynamic remodeling during tissue morphogenesis and repair. Many cell-cell adhesion complexes contain at least one PSD95/Dlg/ZO-1 (PDZ) domain situated between the adhesion molecule and the actin cytoskeleton. However, PDZ-mediated interactions are characteristically nonspecific, weak, and transient, with multiple binding partners per PDZ domain, micromolar dissociation constants, and bond lifetimes of seconds or less. Here, we demonstrate that the bonds between the PDZ domain of the cytoskeletal adaptor protein afadin and the intracellular domains of the adhesion molecules nectin-1 and JAM-A form molecular catch bonds that reinforce in response to mechanical load. In contrast, the bond between the PDZ3-SH3-GUK (PSG) domain of the cytoskeletal adaptor ZO-1 and the JAM-A intracellular domain becomes dramatically weaker in response to ∼2 pN of load, the amount generated by single molecules of the cytoskeletal motor protein myosin II. Thus, physiologically relevant forces can exert dramatic and opposite effects on the stability of two of the major linkages between cell-cell adhesion proteins and the F-actin cytoskeleton. Our data demonstrate that that PDZ domains can serve as force-responsive mechanical anchors at cell-cell adhesion complexes. More broadly, our findings suggest that mechanical force may serve as a previously unsuspected regulator of the hundreds of PDZ-ligand interactions present in animal cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":390439,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":772793,"name":"Matthew DeJong","orcid":"0000-0002-0589-124X","position":1,"is_corresponding":false},{"id":1162737,"name":"Soumya Dutta","orcid":null,"position":2,"is_corresponding":false},{"id":8398,"name":"J. D. Chapman","orcid":"0000-0002-2926-8962","position":3,"is_corresponding":false},{"id":1162738,"name":"Eashani Ghosh","orcid":null,"position":4,"is_corresponding":false},{"id":275519,"name":"Abhishek Singharoy","orcid":"0000-0002-9000-2397","position":5,"is_corresponding":false},{"id":225350,"name":"Alexander R. Dunn","orcid":"0000-0001-6096-4600","position":6,"is_corresponding":false},{"id":225338,"name":"Vipul T. Vachharajani","orcid":"0000-0002-9590-4883","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:37.743462Z","pmid":"37961673","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":[]}