John Burke

Distinct impact of PI(4)P flux on PI(4,5)P2 steady states and oscillations | PNAS Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] regulates indispensable processes such as exocytosis, endocytosis, and actin...

A fascinating look at the frankly bonkers, still-mysterious relationship between master membrane regulator PIP2 and its precursor. Another classic from Min Wu's lab!

The Lipid Interactome: an interactive and open access platform for exploring cellular lipid–protein interactions AbstractSummary. Lipid–protein interactions play essential roles in cellular signaling and membrane dynamics, yet their systematic characterization has lon

Our paper on The Lipid Interactome is now published, and the database is open:

lipidinteractome.org

@ohsummi.bsky.social @ohsunews.bsky.social
@nadlerlab.bsky.social @jeremybaskin.bsky.social

Please RT to spread the word.

doi.org/10.1093/bioi...

cPLA2α targeting to exosomes connects nuclear deformation to LTB4-signaling during neutrophil chemotaxis Nuclear squeezing triggers lipid signals that help neutrophils stay on course through tight spaces.

Another interesting example of how cPLA2 senses nuclear deformation and controls immune cell behaviour. Since the enzyme adsorbs to hydrophobic lipid packing defects, membrane tension and high positive curvature can have similar effects as membrane tension.
www.science.org/doi/10.1126/...

Please spread the word: the Structural Studies Division @mrclmb.bsky.social is looking for a new tenure-track, independent group leader with an exciting plan in any area of Structural (Molecular & Cell) biology, in discovery biology and/or methods development. 🥳

mrc.tal.net/vx/mobile-0/...

Do you want to know more about how Retromer regulates Rab7 activity in yeast? Of course you do. Check out the new collaboration with Andreas Mayer with work led by Catarina Alves and Kevin Chen.

Excited to share our first collaborative paper of the year- a review on the emerging roles of lipids in flavivirus infection, now published in @cp-trendsmicrobiol.bsky.social. Congrats to Judah (postdoc) for spearheading the work!

@ohsunews.bsky.social

www.sciencedirect.com/science/arti...

Have you ever thought about coming to Canada as a researcher? See new programs for established PIs to move to the great north. If you have any questions about possibilities at UVic let me know www.canada.ca/en/impact-pl...

A proximity map of RAB GTPases delineates roles for RAB14 in EARP complex and UHRF1BP1 endosomal recruitments Communications Biology - Proximity labeling proteomics of RAB GTPases identifies an array of neighboring RAB proteins. Functional validation studies reveal links between RAB25 and DENND6A, or...

It is a nice way to end the week: our improved RAB GTPase BioID map now online! www.nature.com/articles/s42... We hope it will be useful to the community, and we're happy to share any reagents!

Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2 The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinos...

www.science.org/doi/10.1126/...

Design, Synthesis, and Biological Evaluation of Mono- and Diamino-Substituted Squaramide Derivatives as Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthase Amides of squaric acid are new drug candidates with activity against mycobacteria. Like the approved drug bedaquiline, these compounds achieve efficacy by inhibiting mycobacterial ATP synthase. Howeve...

Exciting collab with Paul Palme, Peter Imming, & Adrian Richter!
Guided by @courbongautier.bsky.social's structure of myco ATP synthase bound to a squaramide, they have made SQAs that are less toxic, more potent, more stable than AstraZeneca's SQ31f
#MedChem #TB #NTM
pubs.acs.org/doi/full/10....

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/...

Chemical proteomics decrypts the kinases that shape the dynamic human phosphoproteome https://www.biorxiv.org/content/10.1101/2025.11.18.689017v1

Thanks to @alextoker.bsky.social for the motivation to submit this to JBC @asbmbjournals.bsky.social , a great journal, with this being one of the most straightforward and useful manuscript review processes I have gone through in a while

The students working on this were exceptional. Sushant just defended his PhD, and is on the biotech job market with exceptional skills in HDX-MS, protein biophysics, and biochemical assays, with Alex defending in about 15 months looking for cryo EM postdocs. Keep an eye out for their applications!

This was a fun effort involving the Cobb lab for nanobody identification, the Hansen lab for smTIRF, and the Balla lab for cellular assays. This nanobody will be a great way to target selectively TTC7B containing PI4K complexes. We are happy to share, with the sequence in the supplementary as well

Finally in collaboration with Scott Hansen's lab we showed this nanobody blocked EFR3 mediated membrane recruitment using his single molecule TIRF approach, and with Tamas Balla's lab showed this nanobody blocked EFR3 mediated PM recruitment in cells

This nanobody clearly blocked efr3 recruitment in a dose dependent fashion

We specifically wanted this TTC7B selective nanobody to block the ability to bind EFR3, as this is the critical factor in PI4KA plasma membrane recruitment. The cryo EM structure showed a clear steric block of EFR3 binding (based on Sushant and Alex's structure from Science Advances last year)

Sushant and Damilola in my group were running the BLI instrument nonstop to generate all of these curves. Alex was able to solve the cryo EM structure of this nanobody bound to PI4KA-TTC7B

This is important as diseases are caused by hyperactivation of PI4KA, but complete loss is toxic. Therefore we reasoned that we might be able to selectively target unique PI4K regulatory complexes. We developed a nanobody that was highly TTC7B selective

We fully characterised all possible regulatory complexes that can form between all 6 possible combinations of PI4KA regulatory complexes containing EFR3, TTC7 and FAM126 isoforoms

Cool new paper (www.jbc.org/article/S002... from my lab spearheaded by graduate students Sushant @sushantsuresh.bsky.social and Alex @alexlouiseshaw.bsky.social . This was a very cool collaboration with the Scott Hansen, Jennifer Cobb, Tamas Balla labs

Discovery, Optimization, and Anticancer Activity of Lipid-Competitive Pleckstrin Homology Domain-Containing Family A Inhibitors Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has afforded only a limited number of efficacious drugs attributed in large part to on-target toxicity resulting from the pleiotropic effects of these signaling lipids. Targeting the specific phosphoinositide effector pathways via competitive inhibitors of phosphoinositide-recognizing pleckstrin homology (PH) domains represents a relatively unexplored means to achieve greater specificity. Herein, we present the discovery from in silico screening, structure–activity relationship (SAR) optimization, and cellular characterization of novel phosphoinositide-competitive inhibitors of the pleckstrin homology domain-containing A (PLEKHA) family. These compounds induce cytotoxic effects in BRAF and NRAS mutant melanoma cells, consistent with on-target inhibition, and the most potent compound is activated by endogenous esterase activity, suggesting that prodrug esters represent a viable strategy for targeting the phosphoinositide-binding pockets of the PLEKHA family of PH domains.

A while back we found that the lipid-binding protein PLEKHA4 boosts Wnt/β-catenin signaling and drives melanoma growth in vivo. Now, we (Nathan Frederick) identify small-molecule inhibitors of PLEKHA4 & related proteins with anticancer activity in vitro! pubs.acs.org/doi/10.1021/....

Just spent an hour trying to get chatgpt to write a custom zotero script for me. Not super worried about AGI coming anytime soon...

Very cool paper, nice work!

Great visit to the university of torino for a seminar, fun science and great food with good friends

This was part of a special issue to celebrate 50 years since the landmark review from Bob Michell on phosphoinositide signalling. Looking forward to reading the full cohort of papers from this issue

Molecular basis for regulation of the class I phosphoinositide 3-kinases (PI3Ks), and their targeting in human disease The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell fu…

New review out from my lab on class I PI3Ks www.sciencedirect.com/science/arti..., was fun to write where we are and where we are going in PI3K research
Great work from Isobel and Alex in my lab @alexlouiseshaw.bsky.social

Announcing our new PA biosensor, PILS-Nir1 – seen here in HeLa cells during PLC activation #lipidtime #phospholipids

Read the OA paper in JCB

Congrats James