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Jeremy Schmit on the Biophysical Basis of Condensate Functionality

On October 14, Dewpoint and hosted a rising star in the condensates field, Kansas State University’s Jeremy Schmit, as part of our Kitchen Table Talk series. Over the course of his career, Jeremy has been tackling questions about complex protein behavior, which has naturally led him to tackle questions about the complexities of condensates. Most recently, he has worked toward understanding gel-to-liquid phase transitionsamyloid assembly, and all the levels of disorder inside condensates. This talk draws on all of these experiences to delve into the physical principles that enable liquid structures to encode all of the amazing and specific functions that are so critical for life.

Jeremy got the audience thinking and asking questions—so much so that we ran out of time, but he was nice enough to finish answering questions via email. We also got some great answers from Tanja Mittag, who collaborated with Jeremy on some of the work he presented. You can see both of their comments below. We hope the talk gets you thinking too. And if you want yet another way to think about the complex physical behaviors of proteins and amyloids, check out this cool video that Jeremy and his colleagues made. Spoiler alert: Legos.

Jeremy Schmit on the biophysical basis of condensate functionality

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Mark Murcko (00:00:00):
It’s obviously, a great pleasure to welcome Jeremy Schmit today. Jeremy comes from the physics department at Kansas State University. And Jeremy’s whole career, really has been a masterclass at studying the complex behaviors of proteins. And this of course, quite naturally, has led him to phase behavior and thence to cellular condensates. All roads as everyone on this call knows, all roads lead to condensates.

Mark Murcko (00:00:24):
And so, as we now know, condensates are able to carry out many diverse functions. But the question then becomes, what are the common features of condensates? And on the other hand, what makes condensates unique so that one type of condensate is able to carry out certain specific functions that are different from the functions that are carried out by other condensates. And then that leads you to the question of what are the underlying physical properties of the proteins and the nucleic acids at the nanoscale, that then lead to the macroscale behavior that we’re observing in cells? And so these are the kinds of questions that Jeremy has been tackling with great success.

Mark Murcko (00:01:08):
And he’s published on amyloid and huntingtin, looking for the triggers of aggregation and how that connects to disease. He’s collaborated with Tanja Mittag, on the transition between liquid and gel-like states. That’s a JACS paper that came out I think, last year.

Jeremy Schmit (00:01:24):
Beginning of this year, yeah.

Mark Murcko (00:01:26):
Oh, beginning of this year. And then there’s the work with Mike Rosen, which I think is still on bioRxiv. And that helps us to better understand this really interesting way that biological function can emerge out of these condensates, despite the fact that there is disorder in the structural states of the proteins inside of condensates, which is just a fascinating area.

Mark Murcko (00:01:49):
He also on his website, at Kansas State, he has these wonderful little movies that use Legos to explain some of these incredibly complex physical behaviors of proteins. And everyone should definitely check those movies out if you haven’t seen them already.

Mark Murcko (00:02:05):
So Jeremy’s talk today is on the Biophysical Basis of Condensate Functionality and he’ll cover the physical principles that enable these liquid structures to encode all of these amazing and specific functions that are so critical for life. So Jeremy, the floor is yours. And thanks again for doing this.

Jeremy Schmit (00:02:25):
Oh, thanks a lot. And thank you for a wonderful introduction. So the way I want to start out this talk other than showing one of the nicer views that we have here in Kansas, is by confronting my biases here, and maybe confronting is the wrong word, I’m at least going to confess them.

Jeremy Schmit (00:02:50):
And as Mark mentioned, I’m in a physics department. And I very much think like a physicist. And to illustrate that line of thinking here, I’m going to use these two molecules as a test case here. If I’m interested in describing what’s going on with molecules like this, I’m going to start looking at certain physical properties here. And some of the first properties that might pop to mind would be things likehow big are these…


Question from Caitlyn Cardetti: Is there any salt in that mixture?
Response from Jill Bouchard: Yes, about 150 mM NaCl.

Question from Charlotte Fare: Are there mutations to SPOP or DAXX that affect SPOP:DAXX binding that are associated with disease?
Question from Xiao Yan: Can the complex phase behavior of SPOP-DAXX explain the disease mutants?
Jeremy’s Response: See comments by Sarah and Tanja below…

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