Lecithin:cholesterol-acyl-transferase (LCAT) plays a major role in cholesterol metabolism as it is the only extracellular enzyme able to esterify cholesterol. LCAT activity is required for lipoprotein remodelling and, most specifically, for the growth and maturation of HDLs. In fact, genetic alterations affecting LCAT func- tionality may cause a severe reduction in plasma levels of HDL-cholesterol with important clinical consequences. Although several hypotheses were formulated, the exact molecular recognition mechanism between LCAT and HDLs is still unknown. We employed a combination of structural bioinformatics procedures to deepen the insights into the HDL-LCAT interplay that promotes LCAT activation and cholesterol esterification. We have generated a data-driven model of reconstituted HDL (rHDL) and studied the dynamics of an assembled rHDL::LCAT supramolecular complex, pinpointing the conformational changes originating from the interaction between LCAT and apolipoprotein A-I (apoA-I) that are necessary for LCAT activation. Specifically, we propose a mechanism in which the anchoring of LCAT lid to apoA-I helices allows the formation of a hydrophobic hood that expands LCAT active site and shields it from the solvent, allowing the enzyme to process large hydrophobic substrates.

中文翻译：

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rHDL 建模和 LCAT 激活的锚定机制。


卵磷脂：胆固醇酰基转移酶（LCAT）在胆固醇代谢中发挥着重要作用，因为它是唯一能够酯化胆固醇的细胞外酶。 LCAT 活性是脂蛋白重塑所必需的，尤其是 HDL 的生长和成熟所必需的。事实上，影响 LCAT 功能的基因改变可能会导致血浆 HDL 胆固醇水平严重降低，从而产生重要的临床后果。尽管提出了几种假设，但 LCAT 和 HDL 之间的确切分子识别机制仍然未知。我们采用结构生物信息学程序的组合来加深对促进 LCAT 激活和胆固醇酯化的 HDL-LCAT 相互作用的了解。我们生成了重组 HDL (rHDL) 的数据驱动模型，并研究了组装的 rHDL::LCAT 超分子复合物的动力学，查明了源自 LCAT 和载脂蛋白 AI (apoA-I) 之间相互作用的构象变化，这些变化对于LCAT 激活。具体来说，我们提出了一种机制，其中 LCAT 盖锚定到 apoA-I 螺旋上，允许形成疏水罩，扩大 LCAT 活性位点并将其与溶剂隔离，从而允许酶处理大的疏水底物。