9MJ9

Condensing wing of FASN with phosphopantetheine-modified partial ACP

Summary for 9MJ9

• Entry DOI: 10.2210/pdb9mj9/pdb
• EMDB information: 44329 44378
• Descriptor: Fatty acid synthase (2 entities in total)
• Functional Keywords: de novo fatty acid synthesis fatty acid synthase, biosynthetic protein, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 187279.05

Authors

Choi, W.,Li, C.,Chen, Y.,Wang, Y.,Cheng, Y. (deposition date: 2024-12-14, release date: 2025-02-26, Last modification date: 2025-05-21)

Primary citation

Choi, W.,Li, C.,Chen, Y.,Wang, Y.,Cheng, Y.
Structural dynamics of human fatty acid synthase in the condensing cycle.
Nature, 641:529-536, 2025

PubMed Abstract: Long-chain fatty acids are the building blocks of fat in human bodies. In mammals, fatty acid synthase (FASN) contains multiple enzymatic domains to catalyse all chemical reactions needed for de novo fatty acid synthesis. Although the chemical reactions carried out by these enzymatic domains are well defined, how the dimeric FASN with an open architecture continuously catalyses such reactions to synthesize a complete fatty acid remains elusive. Here, using a strategy of tagging and purifying endogenous FASN in HEK293T cells for single-particle cryo-electron microscopy studies, we characterized the structural dynamics of endogenous human FASN. We captured conformational snapshots of various functional substates in the condensing cycle and developed a procedure to analyse the particle distribution landscape of FASN with different orientations between its condensing and modifying wings. Together, our findings reveal that FASN function does not require a large rotational motion between its two main functional domains during the condensing cycle, and that the catalytic reactions in the condensing cycle carried out by the two monomers are unsynchronized. Our data thus provide a new composite view of FASN dynamics during the fatty acid synthesis condensing cycle.

PubMed: 39978408
DOI: 10.1038/s41586-025-08782-w

Experimental method

ELECTRON MICROSCOPY (2 Å)