1 plant hormone receptor ☘️
3,500 mutants, to single-site saturation 🧬
>45,000 binding and abundance measurements 📶

Very happy to present our latest work – where deep mutational scanning meets the world of small molecules.



www.biorxiv.org/content/10.1...



With @benlehner.bsky.social

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GPCR-MAPS is now live! www.biorxiv.org/content/10.1...
A new platform for high resolution functional mapping of GPCRs with massive mutagenesis. We identify the core activation network, residues involved in biased signaling, and generate >7,000 full dose response curves. With @benlehner.bsky.social

+ some great press releases
www.sanger.ac.uk/news_item/sc...

It is a very neat and elegant study which was so fun to work on, and I am very proud to see it out in the world!
@sangerinstitute.bsky.social @ibecbarcelona.eu @crg.eu

12/
Last but by no means least, this was a great team effort - I had the absolute pleasure and privilege of working with brilliant Mireia (X: @mseumaar) and Andre @ajfaure.bsky.social, under the supervision of Ben @benlehner.bsky.social and Benedetta @bennibolo.bsky.social.

11/
The early stages of disease often hold the best targets for intervention. With this new approach, we have turned the invisible visible - and given us a powerful new lens on how Alzheimer’s begins 🧠🔬

10/
Our approach doesn’t just apply to Alzheimer’s disease.
It opens the door to studying dozens of other aggregation-prone proteins linked to disease - many of which have been extremely difficult to study until now.

9/
Why this matters:
✅ Aβ42 mutations cause familial Alzheimer’s disease
✅ Anti-Aβ42 antibodies are the only approved treatments that slow the disease
✅ Our work reveals how Aβ42 starts to go rogue - and gives clues about how to block it

8/
In other words: the seeds of Alzheimer’s are planted in the very first molecular event of nucleation. We have now made a major step in understanding this reaction, which brings us closer to exploring novel therapeutic approaches to prevent it.

7/
This is the first-ever large-scale map of how mutations shape the earliest events in protein aggregation.

6/
We show that a few interactions (energetic couplings) between parts of Aβ42 are significant for the nucleation process. These interactions happen at the C-terminus of the protein and are a subset of those found in the final fibril structures from Alzheimer’s patients’ brains.

5/
By tracking how each mutation affected the speed of fibril formation, we built a complete energetic map of the Aβ42 nucleation reaction. We show that mutations in the latter part of Aβ42 (C-terminus / hydrophobic core) are largely disruptive for nucleation.

4/
So how do we study something we can’t see?
🔬yeast cells
📈kinetic nucleation assay
⚡️high-throughput mutagenesis → 🧬140,000+ combinatorial mutants of Aβ42 - protein that aggregates in Alzheimer’s disease
🧠machine learning and energetic modelling

3/
And yet, it may be the most important step in the disease process, which so far scientists have struggled to study and understand. If we could block nucleation, we might stop Alzheimer’s before it starts 🧠

2/
This “nucleation” step is the molecular switch that kick-starts aggregation and makes it possible for fibrils to spread. To nucleate, amyloid peptides need to go through a high-energy transition state - that is notoriously difficult to capture.

1/
In >50 neurodegenerative diseases - including Alzheimer’s - “rogue” proteins aggregate into harmful structures called amyloid fibrils.
These fibrils are highly stable and toxic. But they don’t appear all at once, first, a few molecules must nucleate - spark 💥before the fire.

Alzheimer’s disease 🧠starts with a molecular domino effect - but what triggers the first piece to fall?
In our new study we cracked open the black box of early protein aggregation, and the findings could reshape how we fight neurodegeneration. 🧵👇

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