🚨 Our story on the TSC:WIPI3 lysosomal-recruitment complex is now live in Science Advances. Equal-first co-authors @luptoncj.bsky.social & Laura D'Andrea. Work lead by @drellisdon.bsky.social. Funding from @deptofdefense.bsky.social & Australian Research Council. www.science.org/doi/10.1126/... - ThreadSky

charlesbj.bsky.social • 98 days ago

🚨 Our story on the TSC:WIPI3 lysosomal-recruitment complex is now live in Science Advances.

Equal-first co-authors @luptoncj.bsky.social & Laura D'Andrea. Work lead by @drellisdon.bsky.social. Funding from @deptofdefense.bsky.social & Australian Research Council.

https://www.science.org/doi/10.1126/sciadv.adr5807

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charlesbj.bsky.social•98 days ago

Whoops! Still learning bsky. Forgot to say #cryoEM ;)

charlesbj.bsky.social•98 days ago

This work was done at the Monash Biomedicine Discovery Institute. @MonashUni

Using our amazing @CryoEM_Monash facility. As always
Hari Venugopal is indispensible to our success!

charlesbj.bsky.social•98 days ago

TSC is conserved back to yeast and is the major regulator of the mTORC1 pathway. We combined protein crystallography, cryo-electron microscopy, cross-linking mass spectrometry, and bioinformatic analysis to obtain the most complete picture of TSC to date.

charlesbj.bsky.social•98 days ago

We propose a docking mechanism that we expect is involved in TSC recruitment to the lysosomal membrane.

charlesbj.bsky.social•98 days ago

Our structure also highlights mutational hotspots, revealing new ways in which TSC mutations can drive disease or dysregulation of this pathway.

charlesbj.bsky.social•98 days ago

Importantly, we discover that TSC recognises mono-phosphorylated phosphatidylinositols. These are known to regulate the mTORC1 pathway as signalling cues for growth.

charlesbj.bsky.social•98 days ago

Finally TSC is extraordinarily flexible and is a massively difficult structural biology target. We had to use all the tricks we know to get this one... Parts of TSC can move by up to 10 nm!!!

chen3dem.bsky.social•97 days ago

Congrats!

charlesbj.bsky.social•97 days ago

And to you too! Your mTORC1 structure is beautiful 😍

brettcollins.bsky.social•98 days ago

Congrats Charles, Chris, Laura, and Andrew and all involved. Lovely structure and technical tour de force.

dwendscheck.bsky.social•98 days ago

I realy like your representation of the frequency of disease relevant mutations and variants in Fig 4A of your paper! I never saw something like this before. But in general a simpler color code without spheres would do the job as well or? Thanks!

charlesbj.bsky.social•98 days ago

Thanks! Yes, certainly you could do it without the spheres, but you'd need a good color code. Personally for me the problem is seeing the magnitude. I find it quite difficult to look at colour alone and see the highly frequent mutations from the less frequent.

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