{"doi":"10.1101/2021.08.28.457928","title":"Mechanistic basis for SNX27-Retromer coupling to ESCPE-1 in promoting endosomal cargo recycling","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Sorting nexin-27 (SNX27)-Retromer is an endosomal sorting complex that orchestrates endosome-to-plasma membrane recycling of hundreds of internalized receptors, channels and transporters, enzymes and adhesion molecules. While SNX27-Retromer is essential for development, subtle functional defects are observed in human disease, most notably neurodegenerative and neurological disorders. Achieving a thorough mechanistic dissection of SNX27-Retromer is central to understanding endosomal sorting in health and disease. Here we combine biochemical, structural and cellular analyses to establish the mechanistic basis through which SNX27-Retromer couples to the membrane tubulating ESCPE-1 complex (Endosomal SNX-BAR sorting complex for promoting exit 1). We show that a conserved surface in the FERM (4.1/ezrin/radixin/moesin) domain of SNX27 directly binds acidic-Asp-Leu-Phe (aDLF) motifs in the disordered amino-termini of the SNX1 and SNX2 subunits of ESCPE-1. This interaction hands-over SNX27-Retromer captured integral membrane proteins into ESCPE-1 tubular profiles to promote their cell surface recycling. Through phylogenetic analysis, we reveal that SNX27:Retromer:ESCPE-1 assembly evolved in a stepwise manner during the early evolution of metazoans, which reflects the increasing complexity of endosomal sorting from the ancestral opisthokont to modern animals.</jats:p>","journal":null,"year":null,"id":621265,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"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":577146,"name":"Qian Guo","orcid":"0000-0002-2133-5358","position":1,"is_corresponding":false},{"id":1604108,"name":"Manuel Gimenez-Andres","orcid":null,"position":2,"is_corresponding":false},{"id":1604109,"name":"Kai-En Chen","orcid":null,"position":3,"is_corresponding":false},{"id":1604110,"name":"Edmund R.R. Moody","orcid":null,"position":4,"is_corresponding":false},{"id":564511,"name":"Ashley J. Evans","orcid":"0000-0002-6658-2176","position":5,"is_corresponding":false},{"id":1036610,"name":"Chris M. Danson","orcid":null,"position":6,"is_corresponding":false},{"id":305978,"name":"Tom A. Williams","orcid":"0000-0003-1072-0223","position":7,"is_corresponding":false},{"id":302574,"name":"Brett M. Collins","orcid":"0000-0002-6070-3774","position":8,"is_corresponding":false},{"id":564513,"name":"Peter J. Cullen","orcid":"0000-0002-9070-8349","position":9,"is_corresponding":false},{"id":1189259,"name":"Boris Simonetti","orcid":"0000-0002-0304-6640","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Mechanistic basis for SNX27-Retromer coupling to ESCPE-1 in promoting endosomal cargo recycling","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Sorting nexin-27 (SNX27)-Retromer is an endosomal sorting complex that orchestrates endosome-to-plasma membrane recycling of hundreds of internalized receptors, channels and transporters, enzymes and adhesion molecules. While SNX27-Retromer is essential for development, subtle functional defects are observed in human disease, most notably neurodegenerative and neurological disorders. Achieving a thorough mechanistic dissection of SNX27-Retromer is central to understanding endosomal sorting in health and disease. Here we combine biochemical, structural and cellular analyses to establish the mechanistic basis through which SNX27-Retromer couples to the membrane tubulating ESCPE-1 complex (Endosomal SNX-BAR sorting complex for promoting exit 1). We show that a conserved surface in the FERM (4.1/ezrin/radixin/moesin) domain of SNX27 directly binds acidic-Asp-Leu-Phe (aDLF) motifs in the disordered amino-termini of the SNX1 and SNX2 subunits of ESCPE-1. This interaction hands-over SNX27-Retromer captured integral membrane proteins into ESCPE-1 tubular profiles to promote their cell surface recycling. Through phylogenetic analysis, we reveal that SNX27:Retromer:ESCPE-1 assembly evolved in a stepwise manner during the early evolution of metazoans, which reflects the increasing complexity of endosomal sorting from the ancestral opisthokont to modern animals.</jats:p>","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W3197457563","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2021,"count":3},{"year":2022,"count":1},{"year":2023,"count":2}],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2021/08/28/2021.08.28.457928.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2021/08/28/2021.08.28.457928.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2021.08.28.457928","host_type":"publisher"},{"url":"https://doi.org/10.1101/2021.08.28.457928","host_type":"repository"}],"fields_of_study":["Cellular transport and secretion","Erythrocyte Function and Pathophysiology","Vascular Malformations Diagnosis and Treatment"],"mesh_terms":[],"keywords":["Retromer","Sorting nexin","Endosome","Cell biology","Biology","Transport protein","Chemistry","Neuroscience","Intracellular"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T13:53:12.833977Z","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":[]}