{"doi":"10.1101/2025.11.05.686565","title":"The Structural Basis for Pacs1-Wdr37 Complex Assembly and Stability","abstract":"ABSTRACT Phosphofurin acidic cluster sorting protein 1 (Pacs1) is a multidomain adaptor proposed to bind transmembrane cargo proteins to facilitate their intracellular trafficking. Pacs1 also forms a complex with WD-repeat protein 37 (Wdr37), which is essential for lymphocyte homeostasis. Despite numerous proposed binding partners, a validated structure for Pacs1-containing protein complexes is lacking. Here, we present the cryo-electron microscopy structure of the Pacs1-Wdr37 complex. Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR), the domain previously linked to cargo recognition. This interaction stabilizes Wdr37 and is critical for the expression of both proteins. A gain-of-function mutation in PACS1 (R203W) causes a highly penetrant neurodevelopmental syndrome. This pathogenic mutation lies on a solvent-exposed surface of the FBR and does not disrupt complex formation. Instead, Pacs1-R203W remains dependent on Wdr37 for stability and its levels can be reduced through targeted Wdr37 proteolytic degradation. Structural homology of the FBR to synaptotagmin C2 domains reveals a previously unrecognized ability of Pacs1 to bind negatively charged phospholipids through a unique positively charged cleft. Together these findings define the structural basis for Pacs1-Wdr37 complex assembly and stability, present potential strategies for Pacs1-mediated neurodevelopmental disease, and suggest novel Pacs1 functions in membrane association.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":580197,"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":0.941,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":812330,"name":"Magdalena Grzemska","orcid":"0000-0002-5306-3553","position":1,"is_corresponding":false},{"id":842568,"name":"Xiong Pi","orcid":"0000-0001-8835-6914","position":2,"is_corresponding":false},{"id":1196790,"name":"Luming Chen","orcid":"0000-0003-0852-5752","position":3,"is_corresponding":false},{"id":1491454,"name":"Michael G. Turner","orcid":null,"position":4,"is_corresponding":false},{"id":889256,"name":"Nagesh Peddada","orcid":"0000-0003-4033-7305","position":5,"is_corresponding":false},{"id":1491455,"name":"Samantha Calvache","orcid":null,"position":6,"is_corresponding":false},{"id":1491456,"name":"Jessica Jia","orcid":null,"position":7,"is_corresponding":false},{"id":51949,"name":"Bruce Beutler","orcid":"0000-0002-3639-246X","position":8,"is_corresponding":false},{"id":228831,"name":"Hao Wu","orcid":"0000-0002-7281-8579","position":9,"is_corresponding":false},{"id":395804,"name":"Evan Nair‐Gill","orcid":"0000-0002-9876-7853","position":10,"is_corresponding":false},{"id":840238,"name":"Le Xiao","orcid":"0000-0001-7277-9170","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:58:38.868285Z","pmid":"41279321","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":[]}