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Analysis of the novel Lipid transfer protein Anchored at Membrane contact sites (LAM) family

Wong, LHY; (2017) Analysis of the novel Lipid transfer protein Anchored at Membrane contact sites (LAM) family. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Membrane contact sites are dynamic structures where two organelles come into close proximity to regulate and facilitate the flow of material and information between them. One type of inter-organelle communication is lipid exchange, which is essential for membrane maintenance and in response to environmental and cellular stimuli. We recently discovered a new family of Lipid transfer proteins Anchored at Membrane contact sites (LAMs) that is present in all eukaryotes. LAM proteins are integral Endoplasmic Reticulum (ER) proteins containing at least one domain that is structurally similar to the StARkin domain superfamily, a specialised fold that can bind amphipathic ligands such as lipids. The budding yeast, Saccharomyces cerevisiae, has six such proteins: Lam1p-6p. Lam1p-4p are located at contacts between the ER and the plasma membrane (PM), and Lam1p-3p are implicated in retrograde sterol traffic between the ER and PM. The PM contains a high concentration of sterol where it increases rigidity by altering the packing characteristics of the phospholipids in the bilayer. Sterol is also important in the ER, where its levels are low but it is both synthesised and sensed. However, the mechanism by which sterol traffics between the ER and the PM is unknown. This investigation characterises the phenotype of yeast delete LAM strains on Amphotericin B, a sterol sequestering antifungal agent and shows that the conserved StARkin domain of LAM proteins is responsible for resistance against Amphotericin B. Aspergillus fumigatus, a filamentous fungus, has two LAM proteins and the removal of AfLamA causes a severe growth phenotype. Also, in vitro studies indicate that LAM StARkin domains have a clear sterol transfer activity and a mutation that can diminish the function in vivo and in vitro has been identified. These findings present a new candidate protein family for intracellular sterol trafficking.

Type: Thesis (Doctoral)
Title: Analysis of the novel Lipid transfer protein Anchored at Membrane contact sites (LAM) family
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Lipid transfer protein, Membrane contact sites, Ergosterol, Sterol, Lipid Binding, LAM, Amphotericin B, Saccharomyces cerevisiae, Endoplasmic Reticulum, Plasma Membrane, Lipids, Aspergillus fumigatus, Cholesterol, Dehydroergosterol, Lam1p, Lam2p, Lam3p, Lam4p, Lam5p, Lam6p, OSH, DUF3074, StART, SRPBCC, StARkin, DUF4782, Ysp1p, Ysp2p, Sip3p, LTC, Liposome, Membrane, Natamycin, Cryptococcus neoformans, Ltc1p, Ltc2p, Ltc3p, Ltc4p
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1560219
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