title: Spot14/Mig12 heterocomplex sequesters polymerization and restrains catalytic function of human acetyl-CoA carboxylase 2.
abstract: 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.
authors.affiliation: Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA; Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sungjo
authors.initials: S
authors.lastname: Park
authors.forename: In-Wook
authors.initials: IW
authors.lastname: Hwang
authors.forename: Yu
authors.initials: Y
authors.lastname: Makishima
authors.forename: Ester
authors.initials: E
authors.lastname: Perales-Clemente
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kato
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Niederländer
authors.forename: Enoch Y
authors.initials: EY
authors.lastname: Park
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000737:chemistry* / Q000378:metabolism*; D002384:Catalysis; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D009687:Nuclear Proteins; C051065:THRSP protein, human; D014157:Transcription Factors; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase
keywords: Mig12; Spot14; Thrsp; acetyl-CoA carboxylase; atomic force microscopy; fatty acid oxidation; protein-protein interactions; silkworm Bombyx mori