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: PCSK9^D374Y 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 PCSK9^D374Y and LDLR. In fact, T9 (GQEQSHQDEGVIVR), an absorbable peptide deriving from lupin β-conglutin, is able to impair the PPI between PCSK9^D374Y 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 PCSK9^D374Y was postulated by in silico tools.

中文翻译：

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功能获得性PCSK9 ^D374Y与低密度脂蛋白受体之间蛋白质-蛋白质相互作用的第一种食品衍生肽抑制剂

前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）参与胆固醇的体内稳态，因为它会诱导低密度脂蛋白受体（LDLR）降解。该蛋白可能带有一些正向或负向突变：PCSK9 ^D374Y是最危险的功能获得突变之一。本文报告了第一个能够抑制PCSK9 ^D374Y和LDLR之间的蛋白质间相互作用（PPI）的食品衍生肽的鉴定。实际上，T9（GQEQSHQDEGVIVR）是一种从羽扇豆β-凝集素衍生而来的可吸收肽，能够通过IC ₅₀破坏PCSK9 ^D374Y和LDLR之间的PPI。值等于285.6±2.46μM。这种抑制的结果是使位于肝细胞膜上的LDLR的蛋白质水平增加高达74.3±4.4％，并使HepG2细胞摄取细胞外低密度脂蛋白的功能恢复到83.1±1.6％。最后，in silico工具假定了T9与PCSK9 ^D374Y上LDLR结合位点的假定结合模式。