| Structural highlights
Function
ASTRC_MOUSE Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (PubMed:30220461). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER (PubMed:30220461). Plays a crucial role in cholesterol homeostasis and has the unique ability to localize to the PM based on the level of membrane cholesterol (PubMed:30220461). In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain (PubMed:30220461). At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER (PubMed:30220461).[1]
Publication Abstract from PubMed
The Aster proteins (encoded by the Gramd1a-c genes) contain a ligand-binding fold structurally similar to a START domain and mediate nonvesicular plasma membrane (PM) to endoplasmic reticulum (ER) cholesterol transport. In an effort to develop small molecule modulators of Asters, we identified 20alpha-hydroxycholesterol (HC) and U18666A as lead compounds. Unfortunately, both 20alpha-HC and U18666A target other sterol homeostatic proteins, limiting their utility. 20alpha-HC inhibits sterol regulatory element-binding protein 2 (SREBP2) processing, and U18666A is an inhibitor of the vesicular trafficking protein Niemann-Pick C1 (NPC1). To develop potent and selective Aster inhibitors, we synthesized a series of compounds by modifying 20alpha-HC and U18666A. Among these, AI (Aster inhibitor)-1l, which has a longer side chain than 20alpha-HC, selectively bound to Aster-C. The crystal structure of Aster-C in complex with AI-1l suggests that sequence and flexibility differences in the loop that gates the binding cavity may account for the ligand specificity for Aster C. We further identified the U18666A analog AI-3d as a potent inhibitor of all three Aster proteins. AI-3d blocks the ability of Asters to bind and transfer cholesterol in vitro and in cells. Importantly, AI-3d also inhibits the movement of low-density lipoprotein (LDL) cholesterol to the ER, although AI-3d does not block NPC1. This finding positions the nonvesicular Aster pathway downstream of NPC1-dependent vesicular transport in the movement of LDL cholesterol to the ER. Selective Aster inhibitors represent useful chemical tools to distinguish vesicular and nonvesicular sterol transport mechanisms in mammalian cells.
Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.,Xiao X, Kim Y, Romartinez-Alonso B, Sirvydis K, Ory DS, Schwabe JWR, Jung ME, Tontonoz P Proc Natl Acad Sci U S A. 2021 Jan 12;118(2). pii: 2024149118. doi:, 10.1073/pnas.2024149118. PMID:33376205[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sandhu J, Li S, Fairall L, Pfisterer SG, Gurnett JE, Xiao X, Weston TA, Vashi D, Ferrari A, Orozco JL, Hartman CL, Strugatsky D, Lee SD, He C, Hong C, Jiang H, Bentolila LA, Gatta AT, Levine TP, Ferng A, Lee R, Ford DA, Young SG, Ikonen E, Schwabe JWR, Tontonoz P. Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell. 2018 Sep 8. pii: S0092-8674(18)31094-8. doi: 10.1016/j.cell.2018.08.033. PMID:30220461 doi:http://dx.doi.org/10.1016/j.cell.2018.08.033
- ↑ Xiao X, Kim Y, Romartinez-Alonso B, Sirvydis K, Ory DS, Schwabe JWR, Jung ME, Tontonoz P. Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms. Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):e2024149118. PMID:33376205 doi:10.1073/pnas.2024149118
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