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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 🧵:
biorxiv.org/content/10.110…
biorxiv.org/content/10.110…
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Stephen Fried JHU retweeted
Protein thiol alterations drive pathologic liquid–liquid phase separation in the aging brain: nature.com/articles/s4159…
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Have you ever wondered how the genetic code got started? So have we ! Now you can read our opinion on it in @TrendsGenetics! @fried_lab @KlaraH_lab @KaHochberg
sciencedirect.com/science/articl…
sciencedirect.com/science/articl…
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Disordered regions are not necessary for phase separation, in fact sometimes they inhibit it. The dimerization domains of PGL-3 are multivalent, necessary, and sufficient for LLPS into P-granules. As we show with @Seydouxlab in this @emboreports paper link.springer.com/article/10.103…
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There is also an important role for the RGG region, which interacts with the dimerization domains and provides greater valency and alters dynamics. But the IDR of PGL-3 is actually solubilizing and does not form forming multivalent interactions
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Congrats to Rimpei & @rx_piyoosh for their hard work on this. Thank you to @NIH_CommonFund, @hhmi_science , @NSF, @SloanFoundation, @dreyfusfndn for support.
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Do you like proteins and beautiful architecture? Join us in Prague for this exciting line-up of speakers in protein science. Kudos to the organizers for putting this together. Registration opens today at pragueproteinspring.cz
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Stephen Fried JHU retweeted
New paper alert 🚀 Our organism-wide single-cell ATAC-seq atlas of mammalian aging is now out in @ScienceMagazine, led by our fantastic graduate student @ziyu__lu from @RockefellerUniv!
science.org/doi/10.1126/sc…
science.org/doi/10.1126/sc…
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I’m so proud of all 4 of you. At such a challenging time for biomedical science your success and hard work is a reminder to us PIs why we do what we do, and why it’s worth it! @fried_lab will miss you but can’t wait to hear what you discover next ❤️!
#FriedLabNews time! Dec-Jan was busy with lots of graduations & @fried_lab alums are off to great things! @haleymoran23 is headed to @berkeleyMCB @MarquseeLab; @_divyayadav is headed to @StJudeResearch O’Reilly lab; April to @EliLillyandCo & Edgar to lead proteomics @HHMIJanelia
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#FriedLabNews time! Dec-Jan was busy with lots of graduations & @fried_lab alums are off to great things! @haleymoran23 is headed to @berkeleyMCB @MarquseeLab; @_divyayadav is headed to @StJudeResearch O’Reilly lab; April to @EliLillyandCo & Edgar to lead proteomics @HHMIJanelia
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This is literally why - in a nutshell - NIGMS moved away from the R01 model in favour of MIRA. enormous labs that work on myriads of loosely related projects are less likely to produce breakthroughs than a group that focuses on a coherent big picture goal.
Ever wondered who the real rockstars of R01s from the past 5 years?
We ranked the most funded PIs in cancer R01s from 2020–2024.
Anyone with persistent effort can (maybe) win one R01. Winning 38–48 of them over 5 years is something else entirely.
R01s flow towards people translate into durable programs.
Durability means:
• hypotheses that age well
• biology that generalizes
• institutions that trust you with long arcs
• and ideas NIH is willing to underwrite repeatedly
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Meet the rockstars, their institutions, and an examplary funded research:
Allen Gao (University of California, Davis @ucdavis)
48 R01 awards | $14.6M
Sample Award: 5R01CA271327
Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer
Xiaoqi Liu (University of Kentucky @universityofky )
46 R01 awards | $20.3M
Sample Award: 5R01CA272483-03
Targeting the PLK1/PDCD4/mTORC2 signaling to treat castration-resistant prostate cancer
Tim Rebbeck (Dana-Farber Cancer Institute @DanaFarber)
43 R01 awards | $10.4M
Sample Award: 5R01CA259200
Genetic and genomic variation in prostate cancer
Shoujiang Gao (University of Pittsburgh School of Medicine @PittTweet)
42 R01 awards | $21.3M
Sample Award: 5R01CA284554
Impact of microbiota on AIDS-Kaposi’s sarcoma development and therapy
James Basilion (Case Western Reserve University School of Medicine @cwru)
39 R01 awards | $18.2M
Sample Award: 5R01CA255925
Highly selective targeted theranostics for prostate cancers
Binghui Shen (City of Hope Beckman Research Institute @cityofhope)
39 R01 awards | $16.6M
Sample Award: 5R01CA233664
DNA repair gene mutations and prostate cancer
Daniela Bota (UC Irvine @UCIMedSchool)
39 R01 awards | $10.4M
Sample Award: 5R01CA263806
Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system
Nan Hao (UC San Diego @UCSDMedSchool)
38 R01 awards | $17.1M
Sample Award: 1R01AG086348
Engineered genetic clocks for control of cellular aging
Zhenghe Wang (Case Western Reserve University School of Medicine @cwru)
38 R01 awards | $16.8M
Sample Award: 4R01CA260629
Role of PTPRT in colon cancer progression and metastasis
Tony Faber (Virginia Commonwealth University School of Medicine)
38 R01 awards | $16.6M
Sample Award: 5R01CA276207
MYCN drives a ferroptotic vulnerability in neuroblastoma
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Fingers crossed…. A little return to normalcy would be a welcome !!
Both chambers of Congress have now passed the FY26 minibus with NIH provisions. The President will sign.
(1) $48.7 billion for NIH
(2) Full IDC recovery
(3) No more multi-year funding
(4) No NIH reorganization, maintaining the current IC structure.
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Stephen Fried JHU retweeted
Limited proteolysis-coupled mass spectrometry captures proteome-wide protein structural alterations and biomolecular condensation in living cells: link.springer.com/article/10.103…
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When PGK tries to refold, it gets tied up in a knot that makes it even MORE stable than its native state. This expands our view of what kinds of misfolded states could accumulate during stress and aging. All the detains in @fried_lab's recent paper.
pubs.acs.org/doi/10.1021/ja…
pubs.acs.org/doi/10.1021/ja…
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Typically we think that misfolded proteins are only "dangerous" if they form an amyloid, otherwise they're cleared by chaperones and UPS. Our data show that soluble misfolded proteins can also be stable, dysfunctional, and evade chaperone detection.
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What does this mean for protein misfolding in aging and disease? Stay tuned, we are on it! Funded by @NSF @NIH_CommonFund @SloanFoundation @dreyfusfndn. Huge congrats to April Xia for pushing through confusing results and making this discovery!
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