New #lipidtime paper out today about a new approach - FACES - for selectively imaging of phospholipids and other biomolecules at spatial resolutions down to individual membrane leaflets
nature.com/articles/s41589-0…
Researchers in @ibudin’s lab have unveiled a new technology with the power to see lipid movement inside cells in unprecedented detail. The tool uses fluorogens to illuminate certain lipids in a cell while other remain dark. Their work appears in @nchembio. bit.ly/4hnDFZG
New #lipidtime paper out today about a new approach - FACES - for selectively imaging of phospholipids and other biomolecules at spatial resolutions down to individual membrane leaflets
nature.com/articles/s41589-0…
We think FACES is a powerful approach for beginning to interrogate the hidden heterogeneity and asymmetry of intracellular membranes. It can also be applied to other molecules accessible to biorthogonal labeling, like intracellular glycans that are difficult to image.
This work was aided greatly by help from the Devaraj (UCSD), Obara (UCSD), and Best (UT Knoxville) labs. Support from @NIH and Allen Family Foundations
The simulations told us how small chemical mods across the pathway altered the conformations of the sterols (TLDR it's about the tail). Perhaps even more profoundly, they suggest what it might really take to make a domain that stays fluid. See vid: piped.video/cH5eDz3e9Xo
This has been one of my favorite projects - it taught me so much about sterols, their metabolism, and the hoops cells go through to make their lipids dance in just the right away. Support from @NSF@NIH (n/n)
In @ScienceAdvances, we report how small chemical modifications in the metabolism of ergosterol are needed for yeast membranes to phase seperate into ordered yet fluid domains science.org/doi/10.1126/scia… (1/n)
We then collaborated with sterol expert Alex Sodt at @NICHD_NIH and his postdoc Laura Lopes Jacobs who built all-atom models for eqch intermediates. We were floored by how well their sims predicted key experimental results, like ordering of DMPC membranes
Turns out the pathway needs to balance it's capacity to order lipids to get to fluid domains, and makes a series of modifications (a methylation, addition and subtraction of double bonds) to hit just the right sweet spot.
Israel found that the pathway builds up to Lo (liquid) domains. Bud it does not do so monotonically: early sterols support domains but they are solid (bad for life). Then domain capacity vanishes. Then right at the end it returns - but now the domains are fluid and functional.
Brave and driven PhD student Israel Juarez-Contreras made every conceivable Erg mutant to generate strains that accumulate each sterol in the pathway, and even some that are not. This allowed him to do a systematic analysis both in love yeast and (once extracted) in liposomes
We wanted to test the Bloch hypothesis in the context of this function. We turned to yeast cells both because of their wonderful genetics but also because their vacuoles mebranes phase seperates into large domains that depend on sterols, just like giant liposomes!
Bloch's hypothesis preceded discovery for another function of sterols: to form Lo phases with saturated phospholipids that form discrete domains, yet are fluid. See seminal work by Keller, Feigenson, London, and many others using synthetic liposomes
Sterols like ergosterol or cholesterol are the most abundant lipids in eukaryotic cells. Yet they are made from very long synthetic routes. Why? Konrad Bloch @MCB_Harvard proposed ~50 years ago that the pathways must continuously shape the sterol to better order phospholipids
Be sure to mark your calendars for March 26th at 12pm ET for the @AsbmbLrd seminar series. We have two great mitochondria-focused lipid talks planned from @JasonCasler1 from Laura Lackner's lab and Kailash Venkatraman from @ibudin's lab. Register here! events.zoom.us/ev/AqPwG5k03R…