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SHR Neuro Cancer Cardio Lipid Metab Microb

Riegler-Berket, L; Wechselberger, L; Cerk, IK; Padmanabha, Das, KM; Viertlmayr, R; Kulminskaya, N; Rodriguez, Gamez, CF; Schweiger, M; Zechner, R; Zimmermann, R; Oberer, M.
Residues of the minimal sequence of G0S2 collectively contribute to ATGL inhibition while C-and N-terminal extensions promote binding to ATGL.
Biochim Biophys Acta Mol Cell Biol Lipids. 2022; 1867(3): 159105 Doi: 10.1016/j.bbalip.2021.159105
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Leading authors Med Uni Graz
Riegler-Berket Lina
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Abstract:
The protein encoded by the G0/G1 switch gene 2 (G0S2) is a potent inhibitor of adipose triglyceride lipase (ATGL) and thus an important regulator of intracellular lipolysis. Since dysfunction of lipolysis is associated with metabolic diseases including diabetes and obesity, inhibition of ATGL is considered a therapeutic strategy. G0S2 interacts with ATGL's patatin-domain to mediate non-competitive inhibition, however atomic details of the inhibition mechanism are incompletely understood. Sequences of G0S2 from higher organisms show a highly conserved N-terminal part, including a hydrophobic region covering amino acids 27 to 42. We show that predicted G0S2 orthologs from platypus, chicken and Japanese rice-fish are able to inhibit human and mouse ATGL, emphasizing the contribution of conserved amino acid to ATGL inhibition. Our site directed mutagenesis and truncation studies give insights in the protein-protein interaction on a per-residue level. We determine that the minimal sequence required for ATGL inhibition ranges from amino acids 20 to 44. Residues Y27, V28, G30, A34 G37, V39 or L42 within this sequence play a substantial role in ATGL inhibition. Furthermore, we show that unspecific interactions of the N-terminal part (amino acids 20-27) of the minimal sequence facilitate the interaction to ATGL. Our studies also demonstrate that full-length G0S2 shows higher tolerance to specific single amino acid exchanges in the hydrophobic region due to the stronger contributions of unspecific interactions. However, exchanges of more than one amino-acid in the hydrophobic region also result in the loss of function as ATGL inhibitor even in the full-length protein.
Find related publications in this database (using NLM MeSH Indexing)
Lipolysis - administration & dosage

Find related publications in this database (Keywords)
Lipolysis
Adipose triglyceride lipase
Protein-protein interaction
Inhibition mechanism
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