Research
We study how lipids are trafficked inside cells. This a basic problem in molecular cell biology, important for understanding the biogenesis of cell membranes and the homeostatic control of their lipid content, as well as protein glycosylation. Our approaches include biochemistry, biophysics, chemical biology, membrane protein reconstitution, quantitative proteomics, single molecule fluorescence, structural biology, and yeast genetics.
Review articles that provide a flavor of our research interests:
Sanyal, Menon (2009) Flipping lipids: why an' what's the reason for? ACS Chem. Biol. 4:895
Holthuis, Menon (2014) Lipid landscapes and pipelines in membrane homeostasis. Nature 510: 48
Kobayashi, Menon (2018) Transbilayer lipid asymmetry. Curr. Biol. 28: R386
Menon (2018) Sterol gradients in cells. Curr. Opin. Cell Biol. 53: 37
Current research projects include:
Discovery of scramblases needed for protein glycosylation in the endoplasmic reticulum
Molecular mechanism of lipid scrambling by newly discovered mitochondrial scramblases (MTCH2 insertase and the VDAC beta-barrel)
Molecular mechanism of lipid scrambling by GPCRs and TMEM16 proteins
FUNDING: Our research is currently supported by the National Institutes of Health, and the Human Frontier Science Program.
GPCR-mediated lipid scrambling
The G protein coupled receptor rhodopsin translocates phospholipids from one side of a membrane bilayer to the other at a unitary rate of >100,000 per second (Menon et al. (2011) Curr Biol (image by Adam Steinberg)). The ‘lipid pathway’ was suggested by molecular dynamics simulations (Morra et al. (2018) Structure). We are testing this pathway experimentally.
A sterol-binding protein at ER-PM contact sites
Fluorescence image of yeast cells. Lam2/Ysp2 (green) is an ER membrane protein found at contact sites between the ER and plasma membrane (red). We are studying how its sterol binding domain is able to exchange sterols between membranes (Gatta et al. (2015) eLife 4:e07253; Jentsch et. al. (2018) J. Biol. Chem., 293:5522; Khelashvili et al. (2019) eLife 8:e53444)
Mannose-P- dolichol scramblase
Mannosylphosphoryldolichol (MPD) is a multifunctional lipid. It provides mannose residues for glycosyltransfer reactions in the lumen of the ER for protein N-glycosylation, O-mannosylation, W-mannosylation and GPI anchoring. It is synthesized on the cytoplasmic face of the ER and transferred to the ER lumen by MPD scramblase, a protein whose molecular identity is not known. Figure taken from Sanyal, Menon (2010) PNAS 107:11289.