{"doi":"10.1101/2022.08.12.503760","title":"Inhibition of Talin-induced Integrin Activation by a Double-hit Stapled Peptide","abstract":"Abstract Integrins are ubiquitously expressed cell-adhesion proteins. Talin is required for integrin activation through an inside-out signaling pathway, during which talin is recruited to the plasma membrane (PM) by RAP1 directly or through its effector, RAP1-Interacting Adaptor Molecule (RIAM). RIAM also activates talin from autoinhibition by binding to talin head domain. A helical talin-binding segment (TBS) in RIAM mediates both talin activation and recruitment by binding to two distinct sites in talin head and rod domains respectively. The bi-specificity of the TBS fragment allows us to develop a new strategy to suppress talin-induced integrin activation through a “double-hit” approach. We designed an experimental peptidomimetic inhibitor by engineering a hydrocarbon “staple” in the helical TBS fragment to mask the integrin binding site in the talin head. The stapled peptide (S-TBS) exhibits a stronger binding affinity with talin and inhibits talin:integrin interaction. Crystal structure of S-TBS in complex with talin rod domains reveals an interface that overlaps with the TBS-binding site in talin. Consistently, S-TBS also exhibits an inhibitory effect on TBS:talin-rod interaction during the PM recruitment of talin. Importantly, S-TBS possesses excellent cell permeability and inhibits integrin activation in a talin-dependent manner. Hence, our results present a novel approach to design a new class of intracellular inhibitors targeting integrin functions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":310576,"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":0.9504,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":408365,"name":"Eun-Ah Cho","orcid":null,"position":1,"is_corresponding":false},{"id":407665,"name":"Pingfeng Zhang","orcid":"0000-0001-5985-4914","position":2,"is_corresponding":false},{"id":407670,"name":"Jinhua Wu","orcid":"0000-0001-5913-0633","position":3,"is_corresponding":false},{"id":1005768,"name":"Tong Gao","orcid":"0000-0002-6879-7680","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:33:19.712967Z","pmid":null,"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":[]}