@article{21912,
  abstract     = {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.},
  author       = {Schultz, Kollin and Costa-Pinheiro, Pedro and Gardner, Lauren and Pinheiro, Laura V. and Ramirez-Solis, Julio and Gardner, Sarah M. and Wellen, Kathryn E. and Marmorstein, Ronen},
  issn         = {1476-4687},
  journal      = {Nature},
  number       = {8062},
  pages        = {520--528},
  publisher    = {Springer Nature},
  title        = {{Snapshots of acyl carrier protein shuttling in human fatty acid synthase}},
  doi          = {10.1038/s41586-025-08587-x},
  volume       = {641},
  year         = {2025},
}

@article{21913,
  abstract     = {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.},
  author       = {Vogt, Austin and Szurgot, Mary and Gardner, Lauren and Schultz, David C. and Marmorstein, Ronen},
  issn         = {1083-351X},
  journal      = {Journal of Biological Chemistry},
  number       = {9},
  publisher    = {Elsevier},
  title        = {{HIRA complex deposition of histone H3.3 is driven by histone tetramerization and histone-DNA binding}},
  doi          = {10.1016/j.jbc.2024.107604},
  volume       = {300},
  year         = {2024},
}