Crystal structure of Spot 14, a modulator of fatty acid synthesis.
Spot 14 (S14) is a protein that is abundantly expressed in lipogenic tissues and is regulated in a manner similar to other enzymes involved in fatty acid synthesis. Deletion of S14 in mice decreased lipid synthesis in lactating mammary tissue, but the mechanism of S14's action is unknown. Here we present the crystal structure of S14 to 2.65 Å and biochemical data showing that S14 can form heterodimers with MIG12. MIG12 modulates fatty acid synthesis by inducing the polymerization and activity of acetyl-CoA carboxylase, the first committed enzymatic reaction in the fatty acid synthesis pathway. Coexpression of S14 and MIG12 leads to heterodimers and reduced acetyl-CoA carboxylase polymerization and activity. The structure of S14 suggests a mechanism whereby heterodimer formation with MIG12 attenuates the ability of MIG12 to activate ACC.
Department of Biochemistry and Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Christopher L
CL
Colbert
Chai-Wan
CW
Kim
Young-Ah
YA
Moon
Lisa
L
Henry
Maya
M
Palnitkar
William B
WB
McKean
Kevin
K
Fitzgerald
Johann
J
Deisenhofer
Jay D
JD
Horton
Hyock Joo
HJ
Kwon
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D005227:Fatty Acids / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D005260:Female; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D008869:Microtubule-Associated Proteins; C485294:Mig12 protein, mouse; D009687:Nuclear Proteins; C501477:Thrsp protein, mouse; D014157:Transcription Factors; D000103:Acetyl-CoA Carboxylase