Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 Mar 2024
21 Mar 2024
Historique:
received:
26
05
2023
accepted:
14
03
2024
medline:
22
3
2024
pubmed:
22
3
2024
entrez:
22
3
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38514628
doi: 10.1038/s41467-024-46937-x
pii: 10.1038/s41467-024-46937-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2516Subventions
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : 10.55776/DOC50
Organisme : Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung)
ID : P30162
Organisme : Karl-Franzens-Universität Graz (University of Graz)
ID : BioHealth
Informations de copyright
© 2024. The Author(s).
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