Spot14/Mig12 heterocomplex sequesters polymerization and restrains catalytic function of human acetyl-CoA carboxylase 2

• Published in: Journal of molecular recognition 2013-12, Vol.26 (12), p.679-688
• Main Authors: Park, Sungjo, Hwang, In-Wook, Makishima, Yu, Perales-Clemente, Ester, Kato, Tatsuya, Niederländer, Nicolas J., Park, Enoch Y., Terzic, Andre
• Format: Article
• Language: English
• Subjects: acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - chemistry; Acetyl-CoA Carboxylase - metabolism; atomic force microscopy; Catalysis; Catalysts; fatty acid oxidation; Fatty Acids - metabolism; Human; Humans; Inhibitors; Microscopy, Atomic Force; Mig12; Nanostructure; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Oxidation-Reduction; Polymerization; Protein Binding; protein-protein interactions; Proteins; Regulators; silkworm Bombyx mori; Special Issue; Spot14; Thrsp; Transcription Factors - chemistry; Transcription Factors - metabolism
• ISSN: 0952-3499; 1099-1352
• DOI: 10.1002/jmr.2313

Acetyl‐CoA carboxylase 2 (ACC2) is an isoform of ACC functioning as a negative regulator of fatty acid β‐oxidation. Spot14, a thyroid hormone responsive protein, and Mig12, a Spot14 paralog, have recently been identified as regulators of fatty acid synthesis targeting ACC1, a distinctive subtype of ACC. Here, we examined whether Spot14/Mig12 modulates ACC2. Nanoscale protein topography mapped putative protein–protein interactions between purified human Spot14/Mig12 and ACC2, validated by functional assays. Human ACC2 displayed consistent enzymatic activity, and homogeneous particle distribution was probed by atomic force microscopy. Citrate‐induced polymerization and enzymatic activity of ACC2 were restrained by the addition of the recombinant Spot14/Mig12 heterocomplex but only partially by the oligo‐heterocomplex, demonstrating that the heterocomplex is a designated metabolic inhibitor of human ACC2. Moreover, Spot14/Mig12 demonstrated a sequestering role preventing an initial ACC2 nucleation step during filamentous polymer formation. Thus, the Spot14/Mig12 heterocomplex controls human ACC2 polymerization and catalytic function, emerging as a previously unrecognized molecular regulator in catalytic lipid metabolism. © 2013 The Authors. Journal of Molecular Recognition published by John Wiley & Sons, Ltd. The putative molecular mechanism in Spot14/Mig12‐depedent multifunctional ACC2 regulation remains unknown. Nanoscale protein topography mapped putative protein‐protein interactions between purified human Spot14/Mig12 and ACC2, validated by functional assays. The Spot14/Mig12 heterocomplex (αβ), not the oligo‐heterocomplex (αβ)6, attenuates ACC2 polymerization and demonstrates a sequestering function, providing evidence for a previously unrecognized molecular regulator useful in modulating catalytic lipid metabolism.