{"doi":"10.1101/2021.10.01.462773","title":"RASopathy Mutations Provide Functional Insight into the BRAF Cysteine-rich Domain and Demonstrate the Importance of Autoinhibition in BRAF Regulation","abstract":"SUMMARY BRAF is frequently mutated in human cancer and the RASopathy syndromes, with RASopathy mutations often observed in the cysteine-rich domain (CRD). Although the CRD participates in phosphatidylserine (PS) binding, the RAS-RAF interaction, and RAF autoinhibition, the impact of these activities on RAF function in normal and disease states is not well-characterized. Here, we analyze a panel of CRD mutations and show that they increase BRAF activity by relieving autoinhibition and/or enhancing PS binding, with relief of autoinhibition being the major factor determining mutation severity in zebrafish models. Further, we show that CRD-mediated autoinhibition is essential for preventing the constitutive plasma membrane localization of BRAF and increased RAS-dependent and RAS-independent function. Comparison of the BRAF- and CRAF-CRDs also indicates that the BRAF-CRD is a stronger mediator of autoinhibition and PS binding, and given the increased catalytic activity of BRAF, our studies reveal a more critical role for CRD-mediated autoinhibition in BRAF regulation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221784,"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":0.9561,"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":814899,"name":"Elizabeth M. Terrell","orcid":null,"position":1,"is_corresponding":false},{"id":725245,"name":"Christine Insinna","orcid":null,"position":2,"is_corresponding":false},{"id":403725,"name":"Constance Agamasu","orcid":null,"position":3,"is_corresponding":false},{"id":822304,"name":"Morgan E. Wagner","orcid":"0000-0003-2848-2892","position":4,"is_corresponding":false},{"id":548158,"name":"Daniel A. Ritt","orcid":null,"position":5,"is_corresponding":false},{"id":822305,"name":"Jim Stauffer","orcid":"0000-0002-1561-772X","position":6,"is_corresponding":false},{"id":346068,"name":"Andrew G. Stephen","orcid":"0000-0002-8259-621X","position":7,"is_corresponding":false},{"id":344167,"name":"Deborah K. Morrison","orcid":"0000-0002-1928-1987","position":8,"is_corresponding":false},{"id":822303,"name":"Russell Spencer-Smith","orcid":"0000-0002-8865-0520","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T23:53:59.302331Z","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":[]}