Kulminskaya_2023_J.Lipid.Res__100491

Reference

Title : Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58) - Kulminskaya_2023_J.Lipid.Res__100491
Author(s) : Kulminskaya N , Rodriguez Gamez CF , Hofer P , Cerk IK , Dubey N , Viertlmayr R , Sagmeister T , Pavkov-Keller T , Zechner R , Oberer M
Ref : J Lipid Res , :100491 , 2023
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 co-activated 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 co-activation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for co-activation 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 co-activation 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 co-activation 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 co-activation 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 co-activation of ATGL.

PubMedSearch : Kulminskaya_2023_J.Lipid.Res__100491
PubMedID: 38135254
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Related information

Gene_locus human-ABHD5    mouse-abhd5
Family human-ABHD5    mouse-abhd5    CGI-58_ABHD5_ABHD4

Citations formats

Kulminskaya N, Rodriguez Gamez CF, Hofer P, Cerk IK, Dubey N, Viertlmayr R, Sagmeister T, Pavkov-Keller T, Zechner R, Oberer M (2023)
Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)
J Lipid Res :100491

Kulminskaya N, Rodriguez Gamez CF, Hofer P, Cerk IK, Dubey N, Viertlmayr R, Sagmeister T, Pavkov-Keller T, Zechner R, Oberer M (2023)
J Lipid Res :100491