Crystal structure of Spot 14, a modulator of fatty acid synthesis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (44), p.18820-18825
• Main Authors: Colbert, Christopher L., Kim, Chai-Wan, Moon, Young-Ah, Henry, Lisa, Palnitkar, Maya, McKean, William B., Fitzgerald, Kevin, Deisenhofer, Johann, Horton, Jay D., Kwon, Hyock Joo
• Format: Article
• Language: English
• Subjects: Acetyl-CoA Carboxylase - genetics; Acetyl-CoA Carboxylase - metabolism; Animals; Antibodies; BASIC BIOLOGICAL SCIENCES; Biochemistry; Biological Sciences; CARBOXYLASE; CARBOXYLIC ACIDS; Cellular immunity; CHO Cells; Cricetinae; Cricetulus; CRYSTAL STRUCTURE; Crystallography, X-Ray; Dimers; ENZYMES; Fatty acids; Fatty Acids - biosynthesis; Fatty Acids - chemistry; Fatty Acids - genetics; Female; Gene expression; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; Hepatocytes; LIPIDS; Liver; MICE; Microtubule-Associated Proteins - chemistry; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Models, Molecular; Monomers; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; POLYMERIZATION; Protein Structure, Tertiary; Protein synthesis; PROTEINS; Small interfering RNA; Structure-Activity Relationship; SYNTHESIS; Tissues; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1012736107

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.