Year: 2016
Type: article
Abstract: Introduction: Lipid signaling refers to events involving lipid messengers that bind proteins, which in turn mediate the effects of these lipids on specific cellular responses. The identification of lipid messengers and mechanisms of their interactions with the target proteins are the main pillars of understanding lipid signaling. Lipids function as signals in two ways: (i) chemical modifications of lipids, and (ii) asymmetric distribution of lipids. Methodology: We utilized computational approaches, including molecular docking, molecular dynamics simulations and bioinformatics, to explore the mechanism of lipid signaling in several cellular pathways. Oxygenated (ox-)lipid signaling in anti-cancer immunity: Oxygenation is the major metabolic modification generating numerous new molecular species of lipids, which can be involved in signaling processes. The structural role of ox-lipids in lipid droplets (LDs) present in tumor environments was examined. The presence of polar oxygenated functional group(s) in oxygenated lipids (ox-lipids) resulted in to their localization in the LD surface. We then explored possible interactions of ox-lipids with the heat shock protein 70 (HSP70), one of the key-proteins in antigen-cross presentation. Our data revealed that HSP70 specifically recognizes the neutral ox-lipids on the LD surface leading to tight binding and deep penetration into the phospholipid monolayer of the LD. Lipoxygenase-driven phospholipid peroxidation signaling: we explored the catalytic and inhibition mechanisms of lipoxygenases (LOX’s), the main generators of ox-lipids in ferroptosis iv cell death. We revealed the mechanism of peroxidation of esterified fatty acid via LOX’s and provided a possible mechanism of inhibition of LOX’s, particularly by vitamin E’s. Lipid signaling due to asymmetric distribution of cardiolipin: The mitochondrial signature phospholipid, cardiolipin (CL), is asymmetrically distributed in the inner mitochondrial membrane. CL asymmetry is disrupted through a process called “CL externalization”, which can be recognized by many proteins. We described the molecular details of cardiolipin interactions with cytochrome c and LC3, the key players of apoptosis and mitophagy pathways, respectively. The CL-binding site(s) on these proteins were identified. Our data suggested that the strong interactions of cyt-c/LC3 with CL-containing membranes lead to CL clustering. This clustering in turn induces a negative curvature on the membrane surface.
Author: Dariush Mohammadyani
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2434242625