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Structure and molecular organization of mammalian fatty acid synthase

Nature Structural & Molecular Biology volume 12, pages 225–232 (2005)Cite this article

Abstract

De novo synthesis of fatty acids in the cytosol of animal cells is carried out by the multifunctional, homodimeric fatty acid synthase (FAS). Cryo-EM analysis of single FAS particles imaged under conditions that limit conformational variability, combined with gold labeling of the N termini and structural analysis of the FAS monomers, reveals two coiled monomers in an overlapping arrangement. Comparison of dimeric FAS structures related to different steps in the fatty acid synthesis process indicates that only limited local rearrangements are required for catalytic interaction among different functional domains. Monomer coiling probably contributes to FAS efficiency and provides a structural explanation for the reported activity of a FAS monomer dimerized to a catalytically inactive partner. The new FAS structure provides a new paradigm for understanding the architecture of FAS and the related modular polyketide synthases.

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Figure 1: Two models for organization of FAS.
Figure 2: Structure and conformational variability of FAS in projection.
Figure 3: Structure of FAS mutants in the presence of substrates.
Figure 4: Three-dimensional structure of FAS.
Figure 5: Structures of FAS monomer and DBP crosslinked FAS monomer, and a possible correlation to the structure of the FAS dimer.
Figure 6: Localization of the FAS N termini by labeling with a gold cluster.

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Acknowledgements

F.J.A. is a scholar of the Leukemia and Lymphoma Society of America. Work in the laboratory of S.S. is supported by US National Institutes of Health grant DK16073.

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Authors and Affiliations

  1. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Francisco J Asturias, James Z Chadick, Iris K Cheung & Helga Stark

  2. Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, 94609, California, USA

    Andrzej Witkowski, Anil K Joshi & Stuart Smith

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Correspondence to Francisco J Asturias.

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Supplementary information

Supplementary Fig. 1

Raw images of FAS particles. (PDF 715 kb)

Supplementary Fig. 2

Characteristics of final ice-FAS reconstruction from unstained specimens. (PDF 96 kb)

Supplementary Methods (PDF 29 kb)

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Asturias, F., Chadick, J., Cheung, I. et al. Structure and molecular organization of mammalian fatty acid synthase. Nat Struct Mol Biol 12, 225–232 (2005). https://doi.org/10.1038/nsmb899

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