Luca Laraia

Organelle-Targeted Laurdans Measure Heterogeneity in Subcellular Membranes and Their Responses to Saturated Lipid Stress Organelles feature characteristic lipid compositions that lead to differences in membrane properties. In cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to lipid packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells; therefore, it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out the membrane packing of individual cellular organelles. The set of organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes, and Golgi compartments with high specificity while retaining the spectral resolution needed to detect biological changes in membrane ordering. We show that ratiometric imaging with OTLs can resolve membrane heterogeneity within organelles as well as changes in lipid packing resulting from inhibition of trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While the ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application in interrogating lipid dysregulation.

The 4 chemically targeted Laurdan derivatives (for mitochondria, ER, lyso/endosomes, and the Golgi) that we published last year are now available (at a pretty reasonable price) from Avanti Polar Lipids (cat #880194, 880197, 880193, 880196). These have been very popular! pubs.acs.org/doi/full/10....

Profiling the proteome-wide selectivity of diverse electrophiles - Nature Chemistry Covalent inhibitors are powerful entities in drug discovery. Now the amino acid selectivity and reactivity of a diverse electrophile library have been assessed proteome-wide using an unbiased workflow...

How can we study target engagement and selectivity of covalent inhibitors? Which electrophilic probes are best suited to study a certain amino acid?

Our study on "Profiling the proteome-wide selectivity of diverse electrophiles" is published in Nature Chemistry.(1/7)

www.nature.com/articles/s41...

Thanks Oliver! We have thought of this - more detailed reply to follow in reply to your message :)

Finally, thanks to DTU Chemistry, @novo-nordisk.bsky.social and @carlsbergfondet.dk for support and funding! (4/4)

Great support by NianzheHe, Maria Lillevang Madsen, Matilde Nielsen and Hogan Bryce-Rogers from our group too! This work was a fantastic collaboration with the labs of David Wiemer and John Beutler, made all the compounds and screened them in the NCI-60 panel! (3/4)

The work, led brilliantly by Laura Depta, includes biophysical profiling against our in vitro panel of sterol transport proteins, molecular docking to rationalise SAR, cellular target engagement and selectivity, as well as on-target phenotypic changes and cytotoxicity. (2/4)

Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein (OSBP) Schweinfurthins (SWs) are natural products isolated from the plant genus Macaranga which display a unique cytotoxicity profile in human cancer cell lines with low nanomolar potency. Their known target...

Happy to share our latest paper in @rscmedchem.rsc.org as part of their 5-year anniversary collection! We carried out comprehensive SAR analysis of natural and synthetic analogues of the #Schweinfurthins, highly potent and selective inhibitors of #OSBP! (1/n) pubs.rsc.org/en/content/a...

Opticial Control of Cholesterol, attempting to stay as close to the original as possible. Congratulations to Michael Zott, who defined and spearheaded this study, and to our wonderful collaborator Luca Laraia!

And the saga continues! Our collaborative work with outstanding Justin Korfhage & Thomas Melia’s lab in PNAS shows that ATG2A transfers triglycerides and does so bidirectionally! An exciting twist in our understanding of lipid transport.
Definitely worth a deep read:
www.pnas.org/doi/10.1073/...

I am excited to see this collaboration develop, and am personally pleased to work and publish with one of a total synthesis and chem bio legend @dirktrauner.bsky.social! (3/3)

Led by Michael Zott, with excellent work from Laura Depta from our group, we show that potency against sterol transport proteins OSBP, ORP1 and ORP2 can be modulated by photoswitching azobenzene containing sterols. (2/3)

Development of Photoswitchable Cholesterol Derivatives through Side Chain Replacement Cholesterol is ubiquitous in biology, shaping membrane properties and serving as a biosynthetic precursor for essential signaling molecules and hormones─and, in some contexts, acting as a signaling mo...

Delighted to have collaborated with the @dirktrauner.bsky.social lab on the development and characterisation of #photoswitchable #cholesterol derivatives, now out in @jacs.acspublications.org! (1/3) pubs.acs.org/doi/full/10....

House of VHL meets house of 14-3-3 🤝

Presenting our study “Induced ubiquitination of the partially disordered Estrogen Receptor alpha protein via a 14-3-3-directed molecular glue-based PROTAC design”

🔗https://www.biorxiv.org/content/10.1101/2025.11.17.688825v1

Call for Papers: Lipids and Lipidation | ACS Publications Chemistry Blog This Special Issue in _ACS Chemical Biology_ will highlight the latest advancements and perspectives in the chemical biology of lipids and lipidation. Submit your manuscript by May 31, 2026.

#ACSChemBio and #Biochemistry invite submissions to a special issue on Lipids and Lipidation guest edited by @chembiobryan.bsky.social and me! Find details in the #CallforPapers and submit your exciting findings to one of these journals by May 31, 2026. axial.acs.org/chemical-bio... #lipidtime

T cell cholesterol transport links intestinal immune responses to dietary lipid absorption The intrinsic pathways that control membrane organization in immune cells and their impact on cellular functions are poorly defined. We found that the nonvesicular cholesterol transporter Aster-A link...

amazing #lipidtime story from Tontonoz lab! Lipid scrambling and cholesterol accessibility IN T-CELLS regulates nutrient uptake in small intestine 🤯🤯

Physiology is so weird!
www.science.org/doi/10.1126/...

Hijacking a bacterial ABC transporter for genetic code expansion - Nature Bacterial ATP-binding cassette (ABC) transporters can be utilized and engineered to transport non-canonical amino acids into Escherichia coli for highly efficient synthesis of proteins with novel func...

🚨Our paper is out! 🥳
Hijacking a bacterial ABC transporter for efficient genetic code expansion.
Many congrats to everyone involved - a multi-year effort led by @taruniype.bsky.social @maxfottner.bsky.social
www.nature.com/articles/s41...

it all started years ago with a failed experiment
🧵👇 1/9

Have you published lipid-protein interactome data? Please let us know, we’d love to include it in the repository. The goal is to build a centralized hub for the scientific community.

Huge thanks to Gaelen Guzman, a graduate student/postdoc in the lab who built it from scratch.

Highly recommended PhD position in Copenhagen! Apply now!

PhD fellowship in Organic Synthesis and Supramolecular Chemistry The Department of Chemistry at the University of Copenhagen invites applicants for a PhD fellowship in Organic chemistry with a particular focus on supramolecul

I have a fully funded PhD position available in my group in Copenhagen: candidate.hr-manager.net/ApplicationI...

Cool work! I think we should be looking at targeting PH domains more!

Very exciting work. Shows how interfering with the levels of one lipid class leads to changes of other lipids that are not directly metabolically connected as the cell tries to maintain both lipid flux balance and biophysical membrane properties.

How do cells sense & respond to lipid imbalances? What happens when a disease-relevant enzyme is blocked? Shiying Huang investigates phosphoinositide lipids with the Balla lab & discovers an integrated cellular response that boosts alternate lipid synthesis pathways! www.biorxiv.org/content/10.1...

If you want to do a deep dive into the data – here’s a website where you can browse through all the images, look at every detail and jump right into mass spectrometric lipid flux data:
www.lipidimaging.org

Stunning and hugely influential work - congratulations!

Fantastic work by @nadlerlab.bsky.social and colleagues. A must read for all those interested in lipids and imaging!

Call for 20 Assistant Professor positions Karolinska Institutet is a world-leading medical university with a long and proud history of ground-breaking research. We are now recruiting outstanding early-career researchers with particularly exce...

Wow

Karolinska Institutet is recruiting 20 outstanding early-career researchers for assistant professor positions

ki.se/en/about-ki/...

To clarify: this is a postdoc position.

Postdoctoral fellowship in protein biochemistry and biophysics - DTU Chemistry Do you want to contribute to an exciting chemical biology project? This postdoctoral fellowship deals with the synthesis of probes aimed at studying cholesterol transport proteins in health and diseas...

I am looking to hire a protein #biochemist, #biophysicist or structural biologist: efzu.fa.em2.oraclecloud.com/hcmUI/Candid...

- 2-year position working on lipid transport proteins.
- Experience in protein expression, purification and biochemical and biophysical assay development.
Please share!

It was a pleasure to present at this fantastic conference! Thanks to @rscmedchem.rsc.org for this great opportunity and the award!

Thanks George :)