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Improved Stability of Human CGI-58 Induced by Phosphomimetic S237E Mutation
MIRIAM LIVIER LLAMAS GARCIA
Edgar Daniel Páez Pérez
CLAUDIA GUADALUPE BENITEZ CARDOZA
GABRIELA MARGARITA MONTERO MORAN
SAMUEL LARA GONZALEZ
Acceso Abierto
Atribución-NoComercial-SinDerivadas
https://doi.org/10.1021/acsomega.1c06872
Adipose triglyceride lipase
Protein
Binding
Domain
Solubility
Prediction
Lipolysis
"In lipolysis, the activating function of CGI-58 is regulated by its interaction with perilipin 1 (PLIN1) localized on the lipid droplet (LD), and its release is controlled by phosphorylation. Once lipolysis is stimulated by catecholamines, protein kinase A (PKA)-mediated phosphorylation enables the dissociation of the CGI-58/PLIN1 complex, thereby recruiting adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) to initiate fatty acid release. It has been shown that mouse CGI-58 mutant S239E, which mimics the phosphorylation of this residue, is able to dissociate from the CGI-58/PLIN1 complex and activate ATGL. Here, we analyze the stabilizing effect on human CGI-58 of a triple tryptophan to alanine mutant (3WA) on the LD-binding motif, as well as a quadruple mutant in which the phosphomimetic S237E substitution was introduced to the 3WA construct (3WA/S237E). We found that tryptophan residues promote wild-type (WT) protein aggregation in solution since their substitution for alanine residues favors the presence of the monomer. Our experimental data showed increased thermal stability and solubility of 3WA/S237E protein compared to the 3WA mutant. Moreover, the 3WA/S237E protein showed proper folding and a functional binding site for oleoyl-CoA. The analysis of a bioinformatic three-dimensional (3D) model suggests an intramolecular interaction between the phosphomimetic glutamic acid and a residue of the α/β hydrolase core. This could explain the increased solubility and stability observed in the 3WA/S237E mutant and evidences the possible role of serine 237 phosphorylation."
American Chemical Society
2022
Artículo
Llamas-García ML, Páez-Pérez ED, Benitez-Cardoza CG, Montero-Morán GM, Lara-González S. Improved Stability of Human CGI-58 Induced by Phosphomimetic S237E Mutation. ACS Omega. 2022 Apr 5;7(15):12643-12653. doi: 10.1021/acsomega.1c06872. PMID: 35474805; PMCID: PMC9026008.
QUÍMICA
Versión publicada
publishedVersion - Versión publicada
Aparece en las colecciones: Publicaciones Científicas Biología Molecular

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