Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, because it induces the low-density lipoprotein receptor (LDLR) degradation. This protein may carry some positive or negative mutations: PCSK9D374Y is one of the most dangerous gain-of-function mutations. This paper reports the identification of the first food-derived peptide able to inhibit the protein-protein interaction (PPI) between PCSK9D374Y and LDLR. In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin β-conglutin, is able to impair the PPI between PCSK9D374Y and the LDLR, with an IC50 value equal to 285.6 ± 2.46 μM. The consequence of this inhibition is an increase of the protein level of the LDLR located on hepatic cell membranes up to 74.3 ± 4.4% and the restoration of the functional capability of HepG2 cells to uptake extracellular low-density lipoprotein up to 83.1 ± 1.6%. Finally, the putative binding mode of T9 to the LDLR binding site located on PCSK9D374Y was postulated by in silico tools.
First Food-Derived Peptide Inhibitor of the Protein-Protein Interaction between Gain-of-Function PCSK9D374Y and the Low-Density Lipoprotein Receptor / G. Grazioso, C. Bollati, S. Jacopo, A. Arnoldi, C. Lammi. - In: JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY. - ISSN 0021-8561. - 66:40(2018 Oct 10), pp. 10552-10557. [10.1021/acs.jafc.8b03233]
First Food-Derived Peptide Inhibitor of the Protein-Protein Interaction between Gain-of-Function PCSK9D374Y and the Low-Density Lipoprotein Receptor
G. GraziosoPrimo
;A. ArnoldiPenultimo
;C. Lammi
Ultimo
2018
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, because it induces the low-density lipoprotein receptor (LDLR) degradation. This protein may carry some positive or negative mutations: PCSK9D374Y is one of the most dangerous gain-of-function mutations. This paper reports the identification of the first food-derived peptide able to inhibit the protein-protein interaction (PPI) between PCSK9D374Y and LDLR. In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin β-conglutin, is able to impair the PPI between PCSK9D374Y and the LDLR, with an IC50 value equal to 285.6 ± 2.46 μM. The consequence of this inhibition is an increase of the protein level of the LDLR located on hepatic cell membranes up to 74.3 ± 4.4% and the restoration of the functional capability of HepG2 cells to uptake extracellular low-density lipoprotein up to 83.1 ± 1.6%. Finally, the putative binding mode of T9 to the LDLR binding site located on PCSK9D374Y was postulated by in silico tools.File | Dimensione | Formato | |
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