Why is there so much disorder in eukaryotic proteins? What is its relationship with condensates? Why can some proteins be saved but others get degraded? After years in the making, we think we have answers and they're all connected. Excited to share a 🧵:.

Thank you @JohnsHopkins for featuring our work and @edbites for this piece explaining the importance of protein folding/misfolding for understanding the basis of cognitive decline. A fun one to share with your science enthusiast friends.

It’s a short paper so I’ll let yall read it rather than give a tweetorial 🧵! Tl;dr: a “familiar” glycolytic enzyme from E. coli can misfold in a truly unusual way, forming an altered conformation that is more stable than its own native state.

Just presented for the first time today by April @ProteinSociety who received their young investigator award! #ProudPI #FriedLabNews. Is Anfinsen’s Thermodynamic Hypothesis of protein folding true? We think PGK challenges it in a truly striking way.

Thanks for the shout out Jim @ShorterLab. Hope you find it interesting 😉!.

@fried_lab is proud of @rx_piyoosh Piyoosh Sharma for starting his new role as a Research Assistant Professor with @WashU bioengineering. We’re sad to see you go but excited for what you’ll discover next! Best of luck and keep in touch! @JHUChemistry

A man and his best friend 😆!.#ASMS2025 #Baltimore was a blast…. Thanks everyone for making my first @asmsnews a memorable one! And well done Edgar Manriquez and Haley Moran for excellent talks.

On an unrelated note: I am decamping Twitter/X but will continue to post here a few more times as an off-ramp. If you find our work on protein folding interest, please follow me @friedlab.bsky.social. I am planning to be more active there! 9/9.

We have benefitted immensely from collaboration with Ed O'Brien, and this project was spearheaded by the remarkable team of Yang Jiang and @fried_lab 's April Xia. Thanks to @NSF and @NIH for their support of thsi work. 8/9.

To summarize, we think that entangled states represent a class of misfolding that can explain complex refolding kinetics & why some proteins do not refold efficiently. Since they are not easily caught by chaperones, they may pose dangers to our cells too. 7/9.

We also used two types of structural mass spectrometry, LiP-MS and XL-MS, to characterize the topologically misfolded form of PGK and showed that these features match the entangled conformations from simulations quite well. 6/9

We show this in a few ways. First, Yang ran extensive simulations on PGK, showing it gets entangled, and if you take the trajectories away with entanglements the stretched exponential signature also disappears. 5/9

But if this is true, what are these various non-native states that cannot just sort themselves out and get back on the normal folding path? We think they are "entangled states" or conformations with non-covalent lasso entanglements. 4/9

Physically, this could correspond to a scenario of a rough free energy landscape with many non-native minima that do not easily interconvert and which have a diverse spectrum of rate constants. 3/9

Where do we begin? In the late 90s, protein folders noticed that not all proteins fold with expected single-exponential kinetics. The enzyme from glycolysis, PGK, appears to follow a stretched exponential function instead. 2/9

Excited to share some work in our collaboration between @fried_lab and Ed O'Brien @psu_chemistry, just published in @ScienceAdvances Here we describe the structural basis for stretched exponential kinetics in protein folding. A thread.

Excited to share some work in our collaboration between @fried_lab and Ed O'Brien @psu_chemistry, just published in @ScienceAdvances :. Here we describe the structural basis for stretched exponential kinetics in protein folding. A thread.

And that’s a wrap! It was a lot of work to put together, but was a great conference in the end! Thanks @broadinstitute for hosting @SSP2024. Next year in Italia 🇮🇹!

Congrats to @fried_lab Edgar Manriquez @JHU_Mol_Biophys for winning a poster prize at @SSP2024 for his work with James Berger’s team on TOP2 condensation! #FriedLabNews

RT @theliulab: Deeply honored to receive the MCP Lectureship award at @SSP2024. Thank you for this incredible opportunity to share our work….

Third and final day of #SSP2024. Ed Huttlin ⁦@HMSBioPlex⁩ and Katja Luck ⁦@imbmainz⁩ kick things off modeling the whole human interactome. Integrating mass spec and AI, it feels like the future has come early!