Amino acids stimulate protein partnership

Monika Oberer researches how proteins work in the cell, for a better understanding of the molecular mechanisms of lipid metabolism. Photo: Uni Graz / Kanizaj

It is one of the key enzymes for the lipid catabolism in the body: ATGL (adipose triglyceride lipase). It was discovered at the University of Graz in 2004. Stimulated by its partner protein CGI-58, it ensures the release of fatty acids into the bloodstream. This process is crucial for metabolic balance. Chronically elevated fatty acid levels are the cause of heart disease, fatty liver or diabetes, among other things. Inhibiting ATGL can alleviate these disorders. For new therapeutic approaches, it is therefore crucial to know the molecular mechanisms of action in detail. Scientists at the University of Graz have now discovered amino acids that are required in ATGL to be stimulated by CGI-58. The study was published in the Journal of Lipid Research.

ATGL massively increases its enzymatic activity by binding to CGI-58. This regulates and optimises the performance of this essential cellular machinery for lipid catabolism. The molecular mechanisms that regulate this interaction have so far remained largely unexplained. "We have now identified specific amino acids on a surface region of ATGL that are essential for the efficient stimulation of its activity by the partner protein," explains Monika Oberer, research group leader at the Department of Molecular Biosciences at the University of Graz.

On the way to this finding, the scientists combined biochemical and molecular biological methods with modern AI-based modeling techniques. "When analysing ATGL-like proteins in various organisms, we found amino acids that are always present in mammals, not so in plants and fungi," reports Oberer. From these, the team then identified those involved in the stimulation of ATGL by CGI-58 by using experimental laboratory technologies and complex 3D modeling. "Our study provides a comprehensive functional model for the interaction of partner proteins in lipid metabolism. This significantly improves our understanding of these central cellular processes," says the researcher, emphasising the significance of the publication.

Monika Oberer's research group is part of BioHealth, a Field of Excellence at the University of Graz.

Publication
Unmasking Crucial Residues in Adipose Triglyceride Lipase for Co-Activation with Comparative Gene Identification-58
Natalia Kulminskaya, Carlos Francisco Rodriguez Gamez, Peter Hofer, Ines Kathrin Cerk, Noopur Dubey, Roland Viertlmayr, Theo Sagmeister, Tea Pavkov-Keller, Rudolf Zechner, Monika Oberer
Journal of Lipid Research, DOI: 10.1016/j.jlr.2023.100491

Gudrun Pichler

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