Proteomics

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


ABSTRACT: ATGL is the key enzyme in intracellular lipolysis playing a critical role in metabolic and cardiovascular diseases. ATGL is tightly regulated through a known set of protein-protein interaction partners with activating or inhibiting functions in control of lipolysis. However, the binding mode and protein interaction sites of ATGL and its partners are unknown. Using deep mutational protein interaction perturbation scanning we generated comprehensive profiles of single amino acid variants effecting the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL variants gave a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identified and characterized eleven, highly selective ATGL “switch” mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provided distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When tested for triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants traced to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provided important insights into lipolysis regulation and the impact of mutations in human disease.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Sarah Masser  

LAB HEAD: Ulrich Stelzl

PROVIDER: PXD049436 | Pride | 2024-03-14

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
10_Plin1_77_un_BD2_1_9582.d.rar Other
10_Plin1_77_un_BD2_1_9606.d.rar Other
16_Plin5_77_un_BD8_1_9594.d.rar Other
16_Plin5_77_un_BD8_1_9598.d.rar Other
2_Plin1_77_ind_BC2_1_9564.d.rar Other
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Publications

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

Kohlmayr Johanna M JM   Grabner Gernot F GF   Nusser Anna A   Höll Anna A   Manojlović Verina V   Halwachs Bettina B   Masser Sarah S   Jany-Luig Evelyne E   Engelke Hanna H   Zimmermann Robert R   Stelzl Ulrich U  

Nature communications 20240321 1


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 a  ...[more]

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