[{"date_published":"2025-05-08T00:00:00Z","has_accepted_license":"1","type":"journal_article","title":"Snapshots of acyl carrier protein shuttling in human fatty acid synthase","author":[{"last_name":"Schultz","first_name":"Kollin","full_name":"Schultz, Kollin"},{"last_name":"Costa-Pinheiro","first_name":"Pedro","full_name":"Costa-Pinheiro, Pedro"},{"orcid":"0009-0000-5733-1546","id":"f9dedd98-6d15-11f0-88a5-a7b4143fdec5","first_name":"Lauren","last_name":"Gardner","full_name":"Gardner, Lauren"},{"first_name":"Laura V.","last_name":"Pinheiro","full_name":"Pinheiro, Laura V."},{"first_name":"Julio","last_name":"Ramirez-Solis","full_name":"Ramirez-Solis, Julio"},{"first_name":"Sarah M.","last_name":"Gardner","full_name":"Gardner, Sarah M."},{"full_name":"Wellen, Kathryn E.","first_name":"Kathryn E.","last_name":"Wellen"},{"full_name":"Marmorstein, Ronen","first_name":"Ronen","last_name":"Marmorstein"}],"article_processing_charge":"Yes (in subscription journal)","publication_identifier":{"issn":["0028-0836"],"eissn":["1476-4687"]},"quality_controlled":"1","publication":"Nature","ddc":["572"],"year":"2025","OA_place":"publisher","publisher":"Springer Nature","language":[{"iso":"eng"}],"month":"05","_id":"21912","date_updated":"2026-06-02T14:57:52Z","citation":{"ieee":"K. Schultz <i>et al.</i>, “Snapshots of acyl carrier protein shuttling in human fatty acid synthase,” <i>Nature</i>, vol. 641, no. 8062. Springer Nature, pp. 520–528, 2025.","mla":"Schultz, Kollin, et al. “Snapshots of Acyl Carrier Protein Shuttling in Human Fatty Acid Synthase.” <i>Nature</i>, vol. 641, no. 8062, Springer Nature, 2025, pp. 520–28, doi:<a href=\"https://doi.org/10.1038/s41586-025-08587-x\">10.1038/s41586-025-08587-x</a>.","ama":"Schultz K, Costa-Pinheiro P, Gardner L, et al. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. <i>Nature</i>. 2025;641(8062):520-528. doi:<a href=\"https://doi.org/10.1038/s41586-025-08587-x\">10.1038/s41586-025-08587-x</a>","ista":"Schultz K, Costa-Pinheiro P, Gardner L, Pinheiro LV, Ramirez-Solis J, Gardner SM, Wellen KE, Marmorstein R. 2025. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. Nature. 641(8062), 520–528.","short":"K. Schultz, P. Costa-Pinheiro, L. Gardner, L.V. Pinheiro, J. Ramirez-Solis, S.M. Gardner, K.E. Wellen, R. Marmorstein, Nature 641 (2025) 520–528.","apa":"Schultz, K., Costa-Pinheiro, P., Gardner, L., Pinheiro, L. V., Ramirez-Solis, J., Gardner, S. M., … Marmorstein, R. (2025). Snapshots of acyl carrier protein shuttling in human fatty acid synthase. <i>Nature</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41586-025-08587-x\">https://doi.org/10.1038/s41586-025-08587-x</a>","chicago":"Schultz, Kollin, Pedro Costa-Pinheiro, Lauren Gardner, Laura V. Pinheiro, Julio Ramirez-Solis, Sarah M. Gardner, Kathryn E. Wellen, and Ronen Marmorstein. “Snapshots of Acyl Carrier Protein Shuttling in Human Fatty Acid Synthase.” <i>Nature</i>. Springer Nature, 2025. <a href=\"https://doi.org/10.1038/s41586-025-08587-x\">https://doi.org/10.1038/s41586-025-08587-x</a>."},"page":"520-528","date_created":"2026-05-24T08:25:19Z","volume":641,"article_type":"original","abstract":[{"text":"The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis1. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections2,3. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP+ plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP–DH and ACP–ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.","lang":"eng"}],"OA_type":"hybrid","pmid":1,"oa_version":"Published Version","intvolume":"       641","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)"},"external_id":{"pmid":["39979457 "]},"main_file_link":[{"open_access":"1","url":"https://doi.org/10.1038/s41586-025-08587-x"}],"oa":1,"extern":"1","issue":"8062","doi":"10.1038/s41586-025-08587-x","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","day":"08","publication_status":"published","status":"public"},{"intvolume":"       300","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"external_id":{"pmid":["39059488"]},"abstract":[{"text":"The HIRA histone chaperone complex is comprised of four protein subunits: HIRA, UBN1, CABIN1, and transiently associated ASF1a. All four subunits have been demonstrated to play a role in the deposition of the histone variant H3.3 onto areas of actively transcribed euchromatin in cells. The mechanism by which these subunits function together to drive histone deposition has remained poorly understood. Here we present biochemical and biophysical data supporting a model whereby ASF1a delivers histone H3.3/H4 dimers to the HIRA complex, H3.3/H4 tetramerization drives the association of two HIRA/UBN1 complexes, and the affinity of the histones for DNA drives release of ASF1a and subsequent histone deposition. These findings have implications for understanding how other histone chaperone complexes may mediate histone deposition.","lang":"eng"}],"article_number":"107604","article_type":"original","volume":300,"date_created":"2026-05-24T08:25:45Z","oa_version":"Published Version","pmid":1,"OA_type":"gold","day":"01","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","doi":"10.1016/j.jbc.2024.107604","status":"public","publication_status":"published","oa":1,"extern":"1","main_file_link":[{"url":"https://doi.org/10.1016/j.jbc.2024.107604","open_access":"1"}],"issue":"9","PlanS_conform":"1","quality_controlled":"1","publication_identifier":{"issn":["0021-9258"],"eissn":["1083-351X"]},"article_processing_charge":"Yes","ddc":["572"],"publication":"Journal of Biological Chemistry","has_accepted_license":"1","type":"journal_article","DOAJ_listed":"1","date_published":"2024-09-01T00:00:00Z","author":[{"full_name":"Vogt, Austin","last_name":"Vogt","first_name":"Austin"},{"full_name":"Szurgot, Mary","first_name":"Mary","last_name":"Szurgot"},{"last_name":"Gardner","first_name":"Lauren","id":"f9dedd98-6d15-11f0-88a5-a7b4143fdec5","full_name":"Gardner, Lauren","orcid":"0009-0000-5733-1546"},{"last_name":"Schultz","first_name":"David C.","full_name":"Schultz, David C."},{"first_name":"Ronen","last_name":"Marmorstein","full_name":"Marmorstein, Ronen"}],"title":"HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding","date_updated":"2026-06-02T14:52:50Z","_id":"21913","citation":{"chicago":"Vogt, Austin, Mary Szurgot, Lauren Gardner, David C. Schultz, and Ronen Marmorstein. “HIRA Complex Deposition of Histone H3.3 Is Driven by Histone Tetramerization and Histone-DNA Binding.” <i>Journal of Biological Chemistry</i>. Elsevier, 2024. <a href=\"https://doi.org/10.1016/j.jbc.2024.107604\">https://doi.org/10.1016/j.jbc.2024.107604</a>.","ista":"Vogt A, Szurgot M, Gardner L, Schultz DC, Marmorstein R. 2024. HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding. Journal of Biological Chemistry. 300(9), 107604.","apa":"Vogt, A., Szurgot, M., Gardner, L., Schultz, D. C., &#38; Marmorstein, R. (2024). HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding. <i>Journal of Biological Chemistry</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.jbc.2024.107604\">https://doi.org/10.1016/j.jbc.2024.107604</a>","short":"A. Vogt, M. Szurgot, L. Gardner, D.C. Schultz, R. Marmorstein, Journal of Biological Chemistry 300 (2024).","ieee":"A. Vogt, M. Szurgot, L. Gardner, D. C. Schultz, and R. Marmorstein, “HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding,” <i>Journal of Biological Chemistry</i>, vol. 300, no. 9. Elsevier, 2024.","mla":"Vogt, Austin, et al. “HIRA Complex Deposition of Histone H3.3 Is Driven by Histone Tetramerization and Histone-DNA Binding.” <i>Journal of Biological Chemistry</i>, vol. 300, no. 9, 107604, Elsevier, 2024, doi:<a href=\"https://doi.org/10.1016/j.jbc.2024.107604\">10.1016/j.jbc.2024.107604</a>.","ama":"Vogt A, Szurgot M, Gardner L, Schultz DC, Marmorstein R. HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding. <i>Journal of Biological Chemistry</i>. 2024;300(9). doi:<a href=\"https://doi.org/10.1016/j.jbc.2024.107604\">10.1016/j.jbc.2024.107604</a>"},"month":"09","language":[{"iso":"eng"}],"publisher":"Elsevier","year":"2024","OA_place":"publisher","acknowledgement":"We would like to acknowledge Elliot Dean and Christina Freeman for technical assistance with recombinant protein expression in insect cells and members of the Marmorstein laboratory for many discussions related to this work. Schematic Figures were created with BioRender.com."}]