Faraz Mardakheh
@mardakheh.bsky.social
Associate Professor at the Department of Biochemistry, University of Oxford. Fellow of Brasenose College.
Studying RNA binding proteins in cancer.
https://mardakhehlab.info
https://www.bioch.ox.ac.uk/research/mardakheh
Studying RNA binding proteins in cancer.
https://mardakhehlab.info
https://www.bioch.ox.ac.uk/research/mardakheh
7/
But does this IDR-dependent conformational gating mechanism matter for LARP6 function in cells? The answer is YES! Removing the N-terminal IDR compromises the function of LARP6 in promoting cancer cell viability and 3D invasion. So selective RNA binding is crucial for LARP6 function.
But does this IDR-dependent conformational gating mechanism matter for LARP6 function in cells? The answer is YES! Removing the N-terminal IDR compromises the function of LARP6 in promoting cancer cell viability and 3D invasion. So selective RNA binding is crucial for LARP6 function.
April 15, 2025 at 11:36 PM
7/
But does this IDR-dependent conformational gating mechanism matter for LARP6 function in cells? The answer is YES! Removing the N-terminal IDR compromises the function of LARP6 in promoting cancer cell viability and 3D invasion. So selective RNA binding is crucial for LARP6 function.
But does this IDR-dependent conformational gating mechanism matter for LARP6 function in cells? The answer is YES! Removing the N-terminal IDR compromises the function of LARP6 in promoting cancer cell viability and 3D invasion. So selective RNA binding is crucial for LARP6 function.
6/
Crucially, when the IDR is present, the La-module becomes locked in a conformation that selects for high-affinity RNA targets.
Remove the IDR ➡️ LARP6 is now more dynamic and less selective for high-affinity RNA targets!
Crucially, when the IDR is present, the La-module becomes locked in a conformation that selects for high-affinity RNA targets.
Remove the IDR ➡️ LARP6 is now more dynamic and less selective for high-affinity RNA targets!
April 15, 2025 at 11:36 PM
6/
Crucially, when the IDR is present, the La-module becomes locked in a conformation that selects for high-affinity RNA targets.
Remove the IDR ➡️ LARP6 is now more dynamic and less selective for high-affinity RNA targets!
Crucially, when the IDR is present, the La-module becomes locked in a conformation that selects for high-affinity RNA targets.
Remove the IDR ➡️ LARP6 is now more dynamic and less selective for high-affinity RNA targets!
5/
How does the IDR promote such selective RNA binding? By combining various biophysical methods (CD, SAX, NMR), we show that the IDR functions by restricting the flexibility of its adjacent La-module. Remove it, and the La-module becomes more flexible & promiscuous. So disorder enforces order 🤯!
How does the IDR promote such selective RNA binding? By combining various biophysical methods (CD, SAX, NMR), we show that the IDR functions by restricting the flexibility of its adjacent La-module. Remove it, and the La-module becomes more flexible & promiscuous. So disorder enforces order 🤯!
April 15, 2025 at 11:36 PM
5/
How does the IDR promote such selective RNA binding? By combining various biophysical methods (CD, SAX, NMR), we show that the IDR functions by restricting the flexibility of its adjacent La-module. Remove it, and the La-module becomes more flexible & promiscuous. So disorder enforces order 🤯!
How does the IDR promote such selective RNA binding? By combining various biophysical methods (CD, SAX, NMR), we show that the IDR functions by restricting the flexibility of its adjacent La-module. Remove it, and the La-module becomes more flexible & promiscuous. So disorder enforces order 🤯!
4/
But there is a twist: when we deleted the IDRs, LARP6 still bound RNA — just less selectively.
Deleting the N-terminal IDR made LARP6 footprints on RNA broader and less precise, suggesting this IDR doesn’t boost binding per se, but fine-tunes which RNAs are bound. Like a molecular filter.🎯
But there is a twist: when we deleted the IDRs, LARP6 still bound RNA — just less selectively.
Deleting the N-terminal IDR made LARP6 footprints on RNA broader and less precise, suggesting this IDR doesn’t boost binding per se, but fine-tunes which RNAs are bound. Like a molecular filter.🎯
April 15, 2025 at 11:36 PM
4/
But there is a twist: when we deleted the IDRs, LARP6 still bound RNA — just less selectively.
Deleting the N-terminal IDR made LARP6 footprints on RNA broader and less precise, suggesting this IDR doesn’t boost binding per se, but fine-tunes which RNAs are bound. Like a molecular filter.🎯
But there is a twist: when we deleted the IDRs, LARP6 still bound RNA — just less selectively.
Deleting the N-terminal IDR made LARP6 footprints on RNA broader and less precise, suggesting this IDR doesn’t boost binding per se, but fine-tunes which RNAs are bound. Like a molecular filter.🎯
3/
Enter LARP6: a conserved RBP with a structured La-module and flanking IDRs. Importantly, LARP6 plays a key role in cancer cell viability and invasion.
We asked: can these IDRs bind RNA in vivo? Using a novel mass spec–based RNA-protein contact site mapping method, we found the answer is YES!
Enter LARP6: a conserved RBP with a structured La-module and flanking IDRs. Importantly, LARP6 plays a key role in cancer cell viability and invasion.
We asked: can these IDRs bind RNA in vivo? Using a novel mass spec–based RNA-protein contact site mapping method, we found the answer is YES!
April 15, 2025 at 11:36 PM
3/
Enter LARP6: a conserved RBP with a structured La-module and flanking IDRs. Importantly, LARP6 plays a key role in cancer cell viability and invasion.
We asked: can these IDRs bind RNA in vivo? Using a novel mass spec–based RNA-protein contact site mapping method, we found the answer is YES!
Enter LARP6: a conserved RBP with a structured La-module and flanking IDRs. Importantly, LARP6 plays a key role in cancer cell viability and invasion.
We asked: can these IDRs bind RNA in vivo? Using a novel mass spec–based RNA-protein contact site mapping method, we found the answer is YES!
🚨Thanks to generous support from @cancerresearchuk.org, we have multiple postdoctoral positions available in our lab (www.mardakhehlab.info) @oxfordbiochemistry.bsky.social to study ribosomes synthesis in cancer. Get in touch if you’re interested + RT and spread the word! 📣 #cancer #RNA 🚨
February 5, 2025 at 12:02 AM
🚨Thanks to generous support from @cancerresearchuk.org, we have multiple postdoctoral positions available in our lab (www.mardakhehlab.info) @oxfordbiochemistry.bsky.social to study ribosomes synthesis in cancer. Get in touch if you’re interested + RT and spread the word! 📣 #cancer #RNA 🚨
🚨 Check out our new preprint “An intrinsically disordered RNA-binding region provides local target selectivity and is essential for LARP6 function”, out now: biorxiv.org/content/10.110…
A Big shout out to my amazing student Fede, Sasi, Gian, Mehran, @genophoria.bsky.social, and all the authors!👏
A Big shout out to my amazing student Fede, Sasi, Gian, Mehran, @genophoria.bsky.social, and all the authors!👏
September 21, 2024 at 1:19 PM
🚨 Check out our new preprint “An intrinsically disordered RNA-binding region provides local target selectivity and is essential for LARP6 function”, out now: biorxiv.org/content/10.110…
A Big shout out to my amazing student Fede, Sasi, Gian, Mehran, @genophoria.bsky.social, and all the authors!👏
A Big shout out to my amazing student Fede, Sasi, Gian, Mehran, @genophoria.bsky.social, and all the authors!👏