Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine

Tillman, Matthew C.; Imai, Norihiro; Li, Yue; Khadka, Manoj; Okafor, C. Denise; Juneja, Puneet; Adhiyaman, Akshitha; Hagen, Susan J.; Cohen, David E.; Ortlund, Eric A.

doi:10.1073/pnas.2003877117

Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine

Journal Article · Thu Aug 20 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2003877117· OSTI ID:1664402

^[1]; ^[2]; ^[3]; ^[4]; Okafor, C. Denise ^[1]; ^[5]; Adhiyaman, Akshitha ^[1]; Hagen, Susan J. ^[3]; Cohen, David E. ^[2]; ^[1]

Emory Univ., Atlanta, GA (United States). School of Medicine
Cornell Univ., Ithaca, NY (United States). Weill Medical College
Beth Israel Deaconess Medical Center, Boston, MA (United States)
Emory Univ., Atlanta, GA (United States). Integrated Lipidomics Core
Emory Univ., Atlanta, GA (United States). Robert P. Apkarian Integrated Electron Microscopy Core

Nonshivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold ambient temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally up-regulated in brown adipose tissue upon exposure to the cold and suppresses thermogenesis in order to conserve energy reserves. It hydrolyzes long-chain fatty acyl-CoAs that are derived from lipid droplets, preventing their use as fuel for thermogenesis. In addition to its enzymatic domains, Them1 contains a C-terminal StAR-related lipid transfer (START) domain with unknown ligand or function. By complementary biophysical approaches, we show that the START domain binds to long-chain fatty acids, products of Them1’s enzymatic reaction, as well as lysophosphatidylcholine (LPC), lipids shown to activate thermogenesis in brown adipocytes. Certain fatty acids stabilize the START domain and allosterically enhance Them1 catalysis of acyl-CoA, whereas 18:1 LPC destabilizes and inhibits activity, which we verify in cell culture. Additionally, we demonstrate that the START domain functions to localize Them1 near lipid droplets. Overall, these findings define the role of the START domain as a lipid sensor that allosterically regulates Them1 activity and spatially localizes it in proximity to the lipid droplet.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); Emory Integrated Lipidomics Core

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1664402

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 36 Vol. 117; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Allosteric regulation of thioesterase superfamily member 1 by lipid sensor domain binding fatty acids and lysophosphatidylcholine

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