6gn5 | pdb_00006gn5
CRYSTAL STRUCTURE OF HUMAN GRAMD1C START DOMAIN
Structural highlights
Function[ASTRC_HUMAN] Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (By similarity). 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 (By similarity). Plays a crucial role in cholesterol homeostasis and has the unique ability to localize to the PM based on the level of membrane cholesterol (By similarity). 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 (By similarity). 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 (By similarity).[UniProtKB:Q8CI52] Publication Abstract from PubMedAutophagy mediates the degradation of damaged proteins, organelles and pathogens, and plays a key role in health and disease. Thus, the identification of new mechanisms involved in the regulation of autophagy is of major interest. In particular, little is known about the role of lipids and lipid-binding proteins in the early steps of autophagosome biogenesis. Using target-agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a new class of autophagy inhibitor. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain-containing protein 1A (GRAMD1A, which had not previously been implicated in autophagy), and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a new biological function of GRAMD1A and a new role for cholesterol in autophagy. The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis.,Laraia L, Friese A, Corkery DP, Konstantinidis G, Erwin N, Hofer W, Karatas H, Klewer L, Brockmeyer A, Metz M, Scholermann B, Dwivedi M, Li L, Rios-Munoz P, Kohn M, Winter R, Vetter IR, Ziegler S, Janning P, Wu YW, Waldmann H Nat Chem Biol. 2019 Jul;15(7):710-720. doi: 10.1038/s41589-019-0307-5. Epub 2019 , Jun 20. PMID:31222192[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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