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Fatty Acids Bind to Them1, a Negative Regulator of Thermogenesis in Brown Adipose Tissue
Author(s) -
Tillman Matthew C,
Khadka Manoj,
Okafor Chiamaka Denise,
Juneja Puneet C,
Ortlund Eric A
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.488.14
Subject(s) - thermogenesis , chemistry , biochemistry , fatty acid , adipose tissue , enzyme , brown adipose tissue , thermogenin , biophysics , biology
Obesity and other metabolic diseases have become a global epidemic, greatly increasing in prevalence over the past 30 years. In mammals, brown adipose tissue counteracts obesity through thermogenesis: the burning of fat to produce heat. Thioesterase superfamily member 1 (Them1) is a multi‐domain enzyme in brown adipose tissue that slows down thermogenesis by converting the substrate acyl‐CoA into fatty acids. Additionally, Them1 contains a lipid‐binding StAR‐related lipid transfer (START) domain with an unknown function. We hypothesized that the lipid‐binding START domain controls thermogenesis by functioning as a lipid sensor for the enzymatic domains of Them1. We used mass spectrometry, X‐ray crystallography, and microscale thermophoresis to demonstrate that long‐chained fatty acids (14–20 carbon tail length), products of Them1's enzymatic reaction, bind to the START domain. Additionally, we determined a low‐resolution structure of full‐length Them1 using negative stain electron microscopy and found that Them1 forms a trimer, making contacts between the enzymatic domains. Using this structure, we ran molecular dynamic simulations to compare protein dynamics in the presence and absence of fatty acid. We determined that the largest differences in protein motions were localized to the START domain. In conclusion, we have used a robust, multidisciplinary approach to demonstrate that fatty acids, the product of Them1 enzymatic activity, bind the START domain, making Them1 the first protein of the START domain family identified to bind fatty acids. Additionally, we provide the first preliminary structure of full‐length Them1, which enhances our limited knowledge of multi‐domain thioesterases. Support or Funding Information This study was supported in part by the Emory Integrated Lipidomics Core (EILC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .