Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease.

Autor: Moran MW; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America., Ramirez EP; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America., Zook JD; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America., Saarinen AM; Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona Scottsdale, AZ, United States of America.; Department of Cardiovascular Medicine, Mayo Clinic in Arizona Scottsdale, AZ, United States of America., Baravati B; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America., Goode MR; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America., Laloudakis V; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America., Kaschner EK; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America., Olson TL; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America., Craciunescu FM; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America., Hansen DT; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; Biodesign Center for Innovations in Medicine, Arizona State University, Tempe, AZ, United States of America., Liu J; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States of America., Fromme P; Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, United States of America.; School of Molecular Sciences, Arizona State University, Tempe, AZ, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Jul 14; Vol. 16 (7), pp. e0249164. Date of Electronic Publication: 2021 Jul 14 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0249164
Abstrakt: In the United States non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. It occurs in every age group, but predominantly in people with risk factors such as obesity and type 2 diabetes. NAFLD is marked by fat accumulation in the liver leading to liver inflammation, which may lead to scarring and irreversible damage progressing to cirrhosis and liver failure. In animal models, genetic ablation of the protein G0S2 leads to alleviation of liver damage and insulin resistance in high fat diets. The research presented in this paper aims to aid in rational based drug design for the treatment of NAFLD by providing a pathway for a solution state NMR structure of G0S2. Here we describe the expression of G0S2 in an E. coli system from two different constructs, both of which are confirmed to be functionally active based on the ability to inhibit the activity of Adipose Triglyceride Lipase. In one of the constructs, preliminary NMR spectroscopy measurements show dominant alpha-helical characteristics as well as resonance assignments on the N-terminus of G0S2, allowing for further NMR work with this protein. Additionally, the characterization of G0S2 oligomers are outlined for both constructs, suggesting that G0S2 may defensively exist in a multimeric state to protect and potentially stabilize the small 104 amino acid protein within the cell. This information presented on the structure of G0S2 will further guide future development in the therapy for NAFLD.
Competing Interests: No authors have competing interest.
Databáze: MEDLINE
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