{"doi":"10.1016/j.jbc.2021.101491","title":"AP-3 shows off its flexibility for the cryo-EM camera","abstract":"The tetrameric adaptor protein AP-3 is critical for the transport of proteins to lysosomes and lysosome-related organelles. The structures of homologous adaptors AP-1 and AP-2 have revealed a closed-to-open conformational change upon membrane recruitment and phosphoinositide binding. Recently, Schoppe et al. reported the first cryo-EM structures of AP-3 from budding yeast and described remarkably flexible solution structures that are all in the open conformation. The apparent lack of a closed conformational state, the first such description in the literature, allows AP-3 to be more reliant on cargo interaction for its initial membrane recruitment compared with AP-1. The tetrameric adaptor protein AP-3 is critical for the transport of proteins to lysosomes and lysosome-related organelles. The structures of homologous adaptors AP-1 and AP-2 have revealed a closed-to-open conformational change upon membrane recruitment and phosphoinositide binding. Recently, Schoppe et al. reported the first cryo-EM structures of AP-3 from budding yeast and described remarkably flexible solution structures that are all in the open conformation. The apparent lack of a closed conformational state, the first such description in the literature, allows AP-3 to be more reliant on cargo interaction for its initial membrane recruitment compared with AP-1. The formation of membrane-enclosed transport vesicles (or tubules) typically requires coat proteins such as clathrin to select cargo and facilitate membrane deformation. Clathrin was the first identified vesicle coat protein and associates with a variety of different adaptor proteins (APs) that bind to sorting signals found in cargo proteins (1Traub L.M. Bonifacino J.S. Cargo recognition in clathrin-mediated endocytosis.Cold Spring Harb. Perspect. Biol. 2013; 5a016790Crossref Scopus (178) Google Scholar, 2Sanger A. Hirst J. Davies A.K. Robinson M.S. Adaptor protein complexes and disease at a glance.J. Cell Sci. 2019; 132jcs222992Crossref PubMed Scopus (35) Google Scholar). These APs can be differentially recruited to the Golgi, endosomes, or plasma membrane, providing clathrin the versatility of operating in several different trafficking pathways. The five known tetrameric adaptors, termed AP-1 to AP-5, have similar subunit compositions, with two large subunits bearing long-unstructured linkers attached to “ear” domains (β1–5 and α, γ, δ, ε, or ζ), a medium-sized subunit (μ1–5), and a small subunit (σ1–5). For AP-3, the subunit composition is β3, δ, μ3, and σ3 (2Sanger A. Hirst J. Davies A.K. Robinson M.S. Adaptor protein complexes and disease at a glance.J. Cell Sci. 2019; 132jcs222992Crossref PubMed Scopus (35) Google Scholar). These APs are well conserved, although AP-4 and AP-5 are not present in many model organisms, such as budding yeast and Drosophila. The role AP-3 plays in protein trafficking was illuminated through the characterization of mutations causing changes in eye color in Drosophila (garnet), coat color in mice (mocha, pearl), and mislocalization of alkaline phosphatase in yeast (3Odorizzi G. Cowles C.R. Emr S.D. The AP-3 complex: A coat of many colours.Trends Cell Biol. 1998; 8: 282-288Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Soon after these reports, AP-3 mutations in humans were found to cause Hermansky–Pudlak syndrome, which is characterized by albinism, defects in blood clotting, immunodeficiency, and pulmonary fibrosis. These studies emphasized the importance of AP-3 in sorting proteins to lysosome-like organelles, including melanosomes, platelet-dense granules, lamellar bodies, and the yeast vacuole (4Dell'Angelica E.C. Shotelersuk V. Aguilar R.C. Gahl W.A. Bonifacino J.S. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor.Mol. Cell. 1999; 3: 11-21Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar, 5Feng L. Seymour A.B. Jiang S. To A. Peden A.A. Novak E.K","journal":"Journal of Biological Chemistry","year":2021,"id":205456,"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":2,"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":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":319667,"name":"Todd R. 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