Activity and structure of human acetyl-CoA carboxylase targeted by a specific inhibitor

TY - JOUR

T1 - Activity and structure of human acetyl-CoA carboxylase targeted by a specific inhibitor

AU - Jang, Sori

AU - Gornicki, Piotr

AU - Marjanovic, Jasmina

AU - Bass, Ethan

AU - P. Iurcotta, Toni

AU - Rodriguez, Pedro

AU - Austin, Jotham

AU - Haselkorn, Robert

N1 - Publisher Copyright: © 2018 Federation of European Biochemical Societies

PY - 2018/6

Y1 - 2018/6

N2 - We have studied a series of human acetyl-CoA carboxylase (ACC) 1 and ACC2 proteins with deletions and/or Ser to Ala substitutions of the known phosphorylation sites. In vitro dephosphorylation/phosphorylation experiments reveal a substantial level of phosphorylation of human ACCs produced in insect cells. Our results are consistent with AMPK phosphorylation of Ser 29 , Ser 80 , Ser 1,201 , and Ser 1,216 . Phosphorylation of the N-terminal regulatory domain decreases ACC1 activity, while phosphorylation of residues in the ACC central domain has no effect. Inhibition of the activity by phosphorylation is significantly more profound at citrate concentrations below 2 mm. Furthermore, deletion of the N-terminal domain facilitates structural changes induced by citrate, including conversion of ACC dimers to linear polymers. We have also identified ACC2 amino acid mutations affecting specific inhibition of the isozyme by compound CD-017-0191. They form two clusters separated by 60–90 Å: one located in the vicinity of the BC active site and the other one in the vicinity of the ACC1 phosphorylation sites in the central domain, suggesting a contribution of the interface of two ACC dimers in the polymer to the inhibitor binding site.

AB - We have studied a series of human acetyl-CoA carboxylase (ACC) 1 and ACC2 proteins with deletions and/or Ser to Ala substitutions of the known phosphorylation sites. In vitro dephosphorylation/phosphorylation experiments reveal a substantial level of phosphorylation of human ACCs produced in insect cells. Our results are consistent with AMPK phosphorylation of Ser 29 , Ser 80 , Ser 1,201 , and Ser 1,216 . Phosphorylation of the N-terminal regulatory domain decreases ACC1 activity, while phosphorylation of residues in the ACC central domain has no effect. Inhibition of the activity by phosphorylation is significantly more profound at citrate concentrations below 2 mm. Furthermore, deletion of the N-terminal domain facilitates structural changes induced by citrate, including conversion of ACC dimers to linear polymers. We have also identified ACC2 amino acid mutations affecting specific inhibition of the isozyme by compound CD-017-0191. They form two clusters separated by 60–90 Å: one located in the vicinity of the BC active site and the other one in the vicinity of the ACC1 phosphorylation sites in the central domain, suggesting a contribution of the interface of two ACC dimers in the polymer to the inhibitor binding site.

KW - acetyl-CoA carboxylase

KW - binding site

KW - human

KW - inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85048969503&partnerID=8YFLogxK

U2 - 10.1002/1873-3468.13097

DO - 10.1002/1873-3468.13097

M3 - 文章

C2 - 29772612

AN - SCOPUS:85048969503

SN - 0014-5793

VL - 592

SP - 2048

EP - 2058

JO - FEBS Letters

JF - FEBS Letters

IS - 12

ER -