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Cited by 10Lipid metabolism and biosynthesisLipid metabolism and disordersPeroxisome Proliferator-Activated Receptors

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Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58

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Kulminskaya, Natalia, Rodriguez Gamez, Carlos Francisco, Hofer, Peter, Cerk, Ines Kathrin, Dubey, Noopur, Viertlmayr, Roland, Sagmeister, Theo, Pavkov-Keller, Tea, Zechner, Rudolf, Oberer, Monika·2024·Journal of Lipid Research
DOI 10.1016/j.jlr.2023.100491PMC PMC10828586

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Abstract

Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be coactivated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein coactivation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for coactivation by CGI-58. ATGL variants with amino acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 coactivation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the coactivation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for coactivation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58-mediated coactivation of ATGL.

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Metadata

Authors
Kulminskaya, N., Rodriguez Gamez, C. F., Hofer, P., Cerk, I. K., Dubey, N., Viertlmayr, R., Sagmeister, T., Pavkov-Keller, T., Zechner, R., & Oberer, M.
Affiliations
University of Graz (AT)
Corresponding author
Oberer, Monika
ORCID
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2024-01
Volume
65
Issue
1
Pages
100491
ISSN
0022-2275 (ISSN-L)
DOI
10.1016/j.jlr.2023.100491
PMC
PMC10828586
OpenAlex
W4389990650
Cited by
10
References
3
Citations by year
2026: 3 · 2025: 2 · 2024: 3
FWCI
1.01
Type
journal article
Language
en
Update notices
erratum (2024-08-01)
Open access
Licence
Locations
  • Journal of Lipid Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Austrian Science Fund
  • Land Steiermark
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
adipose triglyceride lipase, CGI-58, coactivation, lipolysis, protein-protein interaction, site-directed mutagenesis, AlphaFold, protein complex structure, energy homeostasis
MeSH terms
Amino Acids, Animals, Artificial Intelligence, Lipase, Lipolysis, Triglycerides, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Mice

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