---
OA_place: publisher
OA_type: hybrid
_id: '21912'
abstract:
- lang: eng
  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.
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Kollin
  full_name: Schultz, Kollin
  last_name: Schultz
- first_name: Pedro
  full_name: Costa-Pinheiro, Pedro
  last_name: Costa-Pinheiro
- first_name: Lauren
  full_name: Gardner, Lauren
  id: f9dedd98-6d15-11f0-88a5-a7b4143fdec5
  last_name: Gardner
  orcid: 0009-0000-5733-1546
- first_name: Laura V.
  full_name: Pinheiro, Laura V.
  last_name: Pinheiro
- first_name: Julio
  full_name: Ramirez-Solis, Julio
  last_name: Ramirez-Solis
- first_name: Sarah M.
  full_name: Gardner, Sarah M.
  last_name: Gardner
- first_name: Kathryn E.
  full_name: Wellen, Kathryn E.
  last_name: Wellen
- first_name: Ronen
  full_name: Marmorstein, Ronen
  last_name: Marmorstein
citation:
  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>
  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>.
  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.
  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.
  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>.
  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.
date_created: 2026-05-24T08:25:19Z
date_published: 2025-05-08T00:00:00Z
date_updated: 2026-06-02T14:57:52Z
day: '08'
ddc:
- '572'
doi: 10.1038/s41586-025-08587-x
extern: '1'
external_id:
  pmid:
  - '39979457 '
has_accepted_license: '1'
intvolume: '       641'
issue: '8062'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1038/s41586-025-08587-x
month: '05'
oa: 1
oa_version: Published Version
page: 520-528
pmid: 1
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
status: public
title: Snapshots of acyl carrier protein shuttling in human fatty acid synthase
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 641
year: '2025'
...
---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
PlanS_conform: '1'
_id: '21913'
abstract:
- lang: eng
  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.'
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.
article_number: '107604'
article_processing_charge: Yes
article_type: original
author:
- first_name: Austin
  full_name: Vogt, Austin
  last_name: Vogt
- first_name: Mary
  full_name: Szurgot, Mary
  last_name: Szurgot
- first_name: Lauren
  full_name: Gardner, Lauren
  id: f9dedd98-6d15-11f0-88a5-a7b4143fdec5
  last_name: Gardner
  orcid: 0009-0000-5733-1546
- first_name: David C.
  full_name: Schultz, David C.
  last_name: Schultz
- first_name: Ronen
  full_name: Marmorstein, Ronen
  last_name: Marmorstein
citation:
  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>
  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>
  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>.
  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.
  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.
  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>.
  short: A. Vogt, M. Szurgot, L. Gardner, D.C. Schultz, R. Marmorstein, Journal of
    Biological Chemistry 300 (2024).
date_created: 2026-05-24T08:25:45Z
date_published: 2024-09-01T00:00:00Z
date_updated: 2026-06-02T14:52:50Z
day: '01'
ddc:
- '572'
doi: 10.1016/j.jbc.2024.107604
extern: '1'
external_id:
  pmid:
  - '39059488'
has_accepted_license: '1'
intvolume: '       300'
issue: '9'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1016/j.jbc.2024.107604
month: '09'
oa: 1
oa_version: Published Version
pmid: 1
publication: Journal of Biological Chemistry
publication_identifier:
  eissn:
  - 1083-351X
  issn:
  - 0021-9258
publication_status: published
publisher: Elsevier
quality_controlled: '1'
status: public
title: HIRA complex deposition of histone H3.3 is driven by histone tetramerization
  and histone-DNA binding
tmp:
  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)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 300
year: '2024'
...