Structure and molecular organization of mammalian fatty acid synthase.
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.
Asturias
Francisco J
FJ
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. asturias@scripps.edu
Chadick
James Z
JZ
Cheung
Iris K
IK
Stark
Helga
H
Witkowski
Andrzej
A
Joshi
Anil K
AK
Smith
Stuart
S
D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D020285:Cryoelectron Microscopy; D019281:Dimerization; D064429:Fatty Acid Synthases / Q000737:chemistry* / Q000235:genetics; D008322:Mammals / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D048630:Polyketide Synthases / Q000737:chemistry; D011487:Protein Conformation; D013379:Substrate Specificity / Q000235:genetics
D048630:Polyketide Synthases; D064429:Fatty Acid Synthases