17β-Estradiol-Induced Conformational Changes of Human Microsomal Triglyceride Transfer Protein: A Computational Molecular Modelling Study

Human microsomal triglyceride transfer protein (hMTP) plays an essential role in the assembly of apoB-containing lipoproteins, and has become an important drug target for the treatment of several disease states, such as abetalipoproteinemia, fat malabsorption and familial hypercholesterolemia. hMTP is a heterodimer composed of a larger hMTPα subunit and a smaller hMTPβ subunit (namely, protein disulfide isomerase, hPDI). hPDI can interact with 17β-estradiol (E₂), an endogenous female sex hormone. It has been reported that E₂ can significantly reduce the blood levels of low-density lipoprotein, cholesterol and triglyceride, and modulate liver lipid metabolism in vivo. However, some of the estrogen's actions on lipid metabolism are not associated with estrogen receptors (ER), and the exact mechanism underlying estrogen's ER-independent lipid-modulating action is still not clear at present. In this study, the potential influence of E₂ on the stability of the hMTP complex is investigated by jointly using multiple molecular dynamics analyses based on available experimental structures. The molecular dynamics analyses indicate that the hMTP complex in the presence of E₂ has reduced interface contacts and surface areas. A steered molecular dynamics analysis shows that the forces required to separate the two subunits (namely, hPDI and hMTPα subunit) of the hMTP complex in the absence of E₂ are significantly higher than the forces required to separate the complex in which its hPDI is already bound with E₂. E₂ makes the interface between hMTPα and hPDI subunits more flexible and less stable. The results of this study suggest that E₂-induced conformational changes of the hMTP complex might be a novel mechanism partly accounting for the ER-independent lipid-modulating effect of E₂.