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Molecular basis for sterol transport by StART‐like lipid transfer domains
Abstract
Lipid transport proteins at membrane contact sites, where two organelles are closely apposed, play key roles in trafficking lipids between cellular compartments while distinct membrane compositions for each organelle are maintained. Understanding the mechanisms underlying non-vesicular lipid trafficking requires characterization of the lipid transporters residing at contact sites. Here, we show that the mammalian proteins in the lipid transfer proteins anchored at a membrane contact site (LAM) family, called GRAMD1a-c, transfer sterols with similar efficiency as the yeast orthologues, which have known roles in sterol transport. Moreover, we have determined the structure of a lipid transfer domain of the yeast LAM protein Ysp2p, both in its apo-bound and sterol-bound forms, at 2.0 Å resolution. It folds into a truncated version of the steroidogenic acute regulatory protein-related lipid transfer (StART) domain, resembling a lidded cup in overall shape. Ergosterol binds within the cup, with its 3-hydroxy group interacting with protein indirectly via a water network at the cup bottom. This ligand binding mode likely is conserved for the other LAM proteins and for StART domains transferring sterols.
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GRAMD1s extract accessible plasma membrane cholesterol for transport to the endoplasmic reticulum via the StART-like domain, which can directly capture and transport sterol across the cytoplasm.
“GRAMD1s then extract accessible PM cholesterol for transport to the ER via the StART‐like domain, which can directly capture and transport sterol across the cytoplasm (Gatta et al, 2018; Horenkamp et al, 2018; Jentsch et al, 2018; Sandhu et al, 2018; Tong et al, 2018; Khelashvili et al, 2019; Naito et al, 2019).”
From Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b (2021) · cites this paper as Horenkamp et al, 2018
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Cited by
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Sandhu, J., Li, S., Fairall, L., Pfisterer, S. G., Gurnett, J. E., Xiao, X., Weston, T. A., Vashi, D., Ferrari, A., Orozco, J. L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.033 · Cited by 287
Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b
Ercan, B., Naito, T., Koh, D. H. Z., Dharmawan, D., & Saheki, Y. (2021) · The EMBO Journal · doi:10.15252/embj.2020106524 · Cited by 132
Metadata
- Authors
- Horenkamp, F. A., Valverde, D. P., Nunnari, J., & Reinisch, K. M.
- Venue
- The EMBO Journal
- Published
- 2018-02-21
- Volume
- 37
- Issue
- 6
- ISSN
- 0261-4189
- 1460-2075
- Cited by
- 113
- References
- 2
- Language
- en
- Funders
- HHS | National Institutes of Health (R01GM80616, R37GM097432, R01GM106019)
- National Institute of General Medical Sciences (P41 GM103403)
- NSF Graduate Research Fellowship
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