{"doi":"10.1101/2021.10.28.466294","title":"Ligand-induced transmembrane conformational coupling in monomeric EGFR","abstract":"Single pass cell surface receptors regulate cellular processes by transmitting ligand-encoded signals across the plasma membrane via changes to their extracellular and intracellular conformations. While receptor-receptor interactions are established as key aspects of transmembrane signaling, the contribution from the single helix of a monomeric receptor has been challenging to isolate due to the complexity and ligand-dependence of the receptor-receptor interactions. By combining membrane nanodiscs produced wtih cell-free expression, single-molecule Förster Resonance Energy Transfer measurements, and molecular dynamics simulations, we report that ligand binding induces intracellular conformational changes within monomeric, full-length epidermal growth factor receptor (EGFR). Our observations establish the existence of extracellular/intracellular conformational coupling within a single receptor molecule. We implicate a series of electrostatic interactions in the conformational coupling and find the coupling is inhibited by targeted therapeutics and mutations that also inhibit phosphorylation in cells. Collectively, these results introduce a facile mechanism to link the extracellular and intracellular regions through the single transmembrane helix of monomeric EGFR, and raise the possibility that intramolecular transmembrane conformational changes are common to single-pass membrane proteins.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":222245,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9441,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":823397,"name":"Raju Regmi","orcid":"0000-0003-4035-0390","position":1,"is_corresponding":false},{"id":245723,"name":"Xingcheng Lin","orcid":"0000-0002-9378-6174","position":2,"is_corresponding":false},{"id":753984,"name":"Courtney A. Dreyer","orcid":null,"position":3,"is_corresponding":false},{"id":823398,"name":"Xuyan Chen","orcid":"0000-0003-1344-1166","position":4,"is_corresponding":false},{"id":823399,"name":"Steven D. Quinn","orcid":"0000-0003-3442-4103","position":5,"is_corresponding":false},{"id":514484,"name":"Wei He","orcid":"0000-0003-2795-0324","position":6,"is_corresponding":false},{"id":270840,"name":"Kermit L. Carraway","orcid":"0000-0003-0664-9591","position":7,"is_corresponding":false},{"id":237118,"name":"Matthew A. Coleman","orcid":"0000-0003-1389-4018","position":8,"is_corresponding":false},{"id":315414,"name":"Bin Zhang","orcid":"0000-0002-3685-7503","position":9,"is_corresponding":false},{"id":494039,"name":"Gabriela S. Schlau‐Cohen","orcid":"0000-0001-7746-2981","position":10,"is_corresponding":false},{"id":823396,"name":"Shwetha Srinivasan","orcid":"0000-0002-8647-6784","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T23:54:03.549854Z","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":[]}