Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis

Johanna M. Kohlmayr, Gernot F. Grabner, Anna Nusser, Anna Höll, Verina Manojlović, Bettina Halwachs, Sarah Masser, Evelyne Jany-Luig, Hanna Engelke, Robert Zimmermann and Ulrich Stelzl ()
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Johanna M. Kohlmayr: University of Graz
Gernot F. Grabner: University of Graz
Anna Nusser: University of Graz
Anna Höll: University of Graz
Verina Manojlović: University of Graz
Bettina Halwachs: University of Graz
Sarah Masser: University of Graz
Evelyne Jany-Luig: University of Graz
Hanna Engelke: University of Graz
Robert Zimmermann: University of Graz
Ulrich Stelzl: University of Graz

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract ATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.

Date: 2024
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DOI: 10.1038/s41467-024-46937-x

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