{"doi":"10.1074/jbc.m117.799114","title":"The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain","abstract":null,"journal":"Journal of Biological Chemistry","year":2017,"id":615075,"datarank":0.4566783656585135,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.0,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":499046,"name":"Lokesh Gakhar","orcid":"0000-0002-3319-1902","position":1,"is_corresponding":false},{"id":751347,"name":"Fletcher E. Bain","orcid":"0000-0003-1682-7144","position":2,"is_corresponding":false},{"id":273535,"name":"Maria Spies","orcid":"0000-0002-7375-8037","position":3,"is_corresponding":false},{"id":49077,"name":"Ernesto J. Fuentes","orcid":"0000-0001-5812-8187","position":4,"is_corresponding":false},{"id":484738,"name":"Zhen Xu","orcid":"0000-0003-1652-5496","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain","abstract":"T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal pleckstrin homology coiled-coiled extension (PH n -CC-Ex) and catalytic Dbl homology and C-terminal pleckstrin homology (DH-PH c ) domain. Previous studies indicate that larger fragments of Tiam1, such as the region encompassing the N-terminal to C-terminal pleckstrin homology domains (PH n -PH c ), are auto-inhibited. However, the domains in this region responsible for inhibition remain unknown. Here, we show that the PH n -CC-Ex domain inhibits Tiam1 GEF activity by directly interacting with the catalytic DH-PH c domain, preventing Rac1 binding and activation. Enzyme kinetics experiments suggested that Tiam1 is auto-inhibited through occlusion of the catalytic site rather than by allostery. Small angle X-ray scattering and ensemble modeling yielded models of the PH n -PH c fragment that indicate it is in equilibrium between \"open\" and \"closed\" conformational states. Finally, single-molecule experiments support a model in which conformational sampling between the open and closed states of Tiam1 contributes to Rac1 dissociation. Our results highlight the role of the PH n -CC-Ex domain in Tiam1 GEF regulation and suggest a combinatorial model for GEF inhibition and activation of the Rac1 signaling pathway.","is_dataset_classified":null,"base_score":3.044522437723423,"endowment":3.044522437723423,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28882897","pmcid":"PMC5663878","openalex_id":"https://openalex.org/W2752164686","authors":[],"funders":[{"funder_name":"Division of Molecular and Cellular Biosciences","grant_id":"MCB-0953080","title":null},{"funder_name":"American Heart Association","grant_id":"0835261N","title":null},{"funder_name":"National Institutes of Health","grant_id":"NIH 5T32GM008365","title":null},{"funder_name":"National Institutes of Health","grant_id":"NIH R01GM108617","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"T32 GM008365","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM108617","title":null}],"total_grants":6,"fwci":1.2167,"citation_percentile":0.7859431,"influential_citations":0,"citation_trend":[{"year":2018,"count":2},{"year":2019,"count":6},{"year":2020,"count":4},{"year":2021,"count":1},{"year":2022,"count":1},{"year":2023,"count":2},{"year":2024,"count":4}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"http://www.jbc.org/article/S0021925820330398/pdf","host_type":"journal"},{"url":"http://www.jbc.org/article/S0021925820330398/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820330398?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820330398?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1074/jbc.M117.799114","host_type":"publisher"},{"url":"https://doi.org/10.1074/jbc.m117.799114","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28882897","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5663878","host_type":"repository"},{"url":"https://www.osti.gov/biblio/1432852","host_type":"repository"}],"fields_of_study":["Protein Kinase Regulation and GTPase Signaling","Cell Adhesion Molecules Research","Receptor Mechanisms and Signaling"],"mesh_terms":["Pleckstrin Homology Domains","T-Lymphoma Invasion and Metastasis-inducing Protein 1","Humans","Kinetics","Protein Binding","X-Ray Diffraction","Signal Transduction","Guanine Nucleotide Exchange Factors","rac1 GTP-Binding Protein"],"keywords":["Pleckstrin homology domain","Guanine nucleotide exchange factor","RAC1","GTPase","Allosteric regulation","Cell biology","Chemistry","Biology","Biochemistry","Stereochemistry","Signal transduction","Receptor","Enzyme kinetics","Auto-inhibition","Small-angle X-ray Scattering (Saxs)","Ras-related C3 Botulinum Toxin Substrate 1 (Rac1)","Guanine Nucleotide Exchange Factor (Gef)","Tiam1","Inhibition Mechanism","Single-molecule Total Internal Reflection Fluorescence Microscopy","In Vitro Gef Assays"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T18:48:05.916844Z","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":[]}