Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease
Abstract
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 oligomersmore »
- Authors:
-
[1];
[1];
[4];
[1]
- Arizona State Univ., Tempe, AZ (United States). Biodesign Center for Applied Structural Discovery. School of Molecular Sciences
- Arizona State Univ., Tempe, AZ (United States). Biodesign Center for Applied Structural Discovery
- Mayo Clinic in Arizona, Scottsdale, AZ (United States). Dept. of Biochemistry and Molecular Biology. Dept. of Cardiovascular Medicine
- Arizona State Univ., Tempe, AZ (United States). Biodesign Center for Applied Structural Discovery. Biodesign Center for Innovations in Medicine
- Mayo Clinic, Rochester, MN (United States). Dept. of Biochemistry and Molecular Biology
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1826793
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 16; Journal Issue: 7; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; NMR spectroscopy; Fatty liver; Lipases; Oligomers; Hydrolases; Light scattering; Small-angle scattering; Escherichia coli
Citation Formats
Moran, Michael W., Ramirez, Elizabeth P., Zook, James D., Saarinen, Alicia M., Baravati, Bobby, Goode, Matthew R., Laloudakis, Vasiliki, Kaschner, Emily K., Olson, Tien L., Craciunescu, Felicia M., Hansen, Debra T., Liu, Jun, and Fromme, Petra. Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease. United States: N. p., 2021.
Web. doi:10.1371/journal.pone.0249164.
Moran, Michael W., Ramirez, Elizabeth P., Zook, James D., Saarinen, Alicia M., Baravati, Bobby, Goode, Matthew R., Laloudakis, Vasiliki, Kaschner, Emily K., Olson, Tien L., Craciunescu, Felicia M., Hansen, Debra T., Liu, Jun, & Fromme, Petra. Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease. United States. https://doi.org/10.1371/journal.pone.0249164
Moran, Michael W., Ramirez, Elizabeth P., Zook, James D., Saarinen, Alicia M., Baravati, Bobby, Goode, Matthew R., Laloudakis, Vasiliki, Kaschner, Emily K., Olson, Tien L., Craciunescu, Felicia M., Hansen, Debra T., Liu, Jun, and Fromme, Petra. Wed .
"Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease". United States. https://doi.org/10.1371/journal.pone.0249164. https://www.osti.gov/servlets/purl/1826793.
@article{osti_1826793,
title = {Biophysical characterization and a roadmap towards the NMR solution structure of G0S2, a key enzyme in non-alcoholic fatty liver disease},
author = {Moran, Michael W. and Ramirez, Elizabeth P. and Zook, James D. and Saarinen, Alicia M. and Baravati, Bobby and Goode, Matthew R. and Laloudakis, Vasiliki and Kaschner, Emily K. and Olson, Tien L. and Craciunescu, Felicia M. and Hansen, Debra T. and Liu, Jun and Fromme, Petra},
abstractNote = {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.},
doi = {10.1371/journal.pone.0249164},
journal = {PLoS ONE},
number = 7,
volume = 16,
place = {United States},
year = {2021},
month = {7}
}
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