Franziska Sendker
@SendkerFL
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postdoc - designing proteins at Dana-Farber/Harvard Medical School | formerly, evolutionary biochemistry at Max PIanck Institute in Marburg
Joined August 2021
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Happy and super excited to share our discovery of a protein fractal! We unravel the surprisingly simple emergence of these marvellous structures and show it might have even been an accident of evolution. Read the full story here
Or just stick around 🧵
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Today I threw whole-cell lysates of a cyanobacterium on a size exclusion column. Look how nicely it separates the different pigment-complexes!! (not at all why i did this experiment but lovely byproduct that made my day 😇)
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Our story started with a simple observation: We found a cyanobacterial citrate synthase (an ordinary enzyme) to form unusually large complexes, increasing in weight in threefold steps. To our great surprise, electron microscopy revealed these as beautifully regular triangles.
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In other news: Finally defended my PhD thesis 🥳
Big thank you to
@KaHochberg
and
@IMPRS_Mic
for all the support and everyone who made it such a special and beautiful day 🥰
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While familiar to everyone that has played Zelda, it is not obvious at all how a protein could assemble into such a structure. The reasons are symmetry constraints that underly all known protein-protein interactions. These render fractal assembly basically impossible.
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Based on our findings we suspect that evolutionary transitions in self-assembly may be more common than expected previously. Perhaps only a small fraction ever become important to their organisms and persist while many others will fade as quickly.
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Based on structures solved via cryo-EM we investigated the assembly principles in detail. The trick the protein employs is based on conformational flexibility of individual subunits. Local symmetries are broken which passivates the triangular edges of the protein complexes.
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Had a lot of fun at
@apfed2022
conference in Bayreuth. Thank you so much to the amazing organizers!
Also, found the most german bus stop there is here 😁
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Had an awesome time at BM29
@esrfsynchrotron
measuring SAXS with
@AnkeWerner
, anton popov and mark tully!
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Our results show that for a short window in history a single amino acid substitution (q18L) was sufficient to trigger the emergence of fractal assembly. This change did not introduce a new contact in the fractal interface but removed a constraint. Everything was already in place.
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This single change conferred all the trappings of a complex biological structure including responsiveness to external triggers. The simple and short evolutionary trajectory makes a non-adaptive, accidental origin of the fractal plausible. Even when looking deceptively adaptive.
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But what does it do? Differences in assembly are often used to regulate an enzyme’s activity. In vitro experiments indicated that this could be the case here: The catalytic efficiency exhibited by fractal complexes is much lower compared to their individual building blocks.
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For starters: What is a fractal again?
Don’t worry, you know them for sure! Fractals exhibit self-similarity over multiple scales meaning individual parts resemble the shape of the whole structure. Famous examples include the Mandelbrot set or the Sierpiński triangle.
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Lastly, huge thank you to
@KaHochberg
and all fantastic collaborators that contributed greatly to make this story possible:
Yat Kei, Thomas, Stefan, Louise, Nils, Wiktoria, Nicole, Eva, María, Karl,
@DSchindler_PDR
@erblabs
@BeneschResearch
@ErikMarklund
@BangeBalcony
@SchullerJm
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All of this was highly indicative of a regulatory mechanism shaped by natural selection. But when we took away the ability to assemble into fractals in vivo, the host cyanobacterium did not care at all. It happily grew just as well as the wild type under all tested conditions.
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Looking into nature we can observe fractal patterns e.g. in river beds or fern leaves. These are not regular though, meaning they do not match exactly at different scales. They are also restricted to macroscopic objects. On a molecular level, natural fractals are unheard of.
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But if not for a beneficial function how does such an intricate assembly emerge in evolution? We approached this question by resurrecting ancestral versions of this enzyme to identify how it evolved from precursors that couldn't form fractals.
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We could even show that distinct molecular triggers can shift the equilibrium between assembly states: high concentration of substrates as well as physiological pH fluctuations of the host organism induce disassembly of the fractal structures into its building blocks.
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Also, shoutout and much love to
@bradyajohnston
for fantastic Blender tutorials for protein structures. The title slide was made using his
#MolecularNodes
addon.
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Join in, will be fun 🙌
We're pleased to announce an exciting new webinar for next month! Join us to hear
@SendkerFL
talk about the discovery of an unprecedented type of homomeric
#protein
assembly, not predicted by known symmetry rules. How? Using
#massphotometry
! Register now -
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@esrfsynchrotron
@mpi_marburg
@Nature
@lightsources
@ESFRI_eu
@KaHochberg
Good times 😊 Big thank you for the opportunity to measure my samples
@esrfsynchrotron
Had an awesome time at BM29
@esrfsynchrotron
measuring SAXS with
@AnkeWerner
, anton popov and mark tully!
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@Archaeon_Alex
@sadie_antine
Good question. But I do not think so - as the name says they are lattices :) We describe the difference to our fractal in figure 2a.
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Finally successfully peer pressured into creating a sErIoUs account
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@schulluc
@frederikschmi
@Trematode12
@NielsOehlmann
@erblabs
@RebeleinLab
Beautiful 🤩 And the structure is also pretty cool!!
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@mosasaurus27
Good question. We did not find any differences on the side of the enzyme besides assembly. Also if we invert the substitution in the wildtype (L18Q) the catalytic properties are the same on the level of hexameric subcomplexes. See in Extended Data Fig. 5
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@Marco_Masi
Quickly get so large that they are difficult to fit into a bacterial cell, we think that they are quite certain an accidental by-product of the unusual symmetry the protein happened to have evolved.
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@JPedroFQueiroz
Hey! Here you can find all the papers that are using mass photometry as a method
And if you want to see/learn yourself, just hit someone up from our lab :)
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@Marco_Masi
Understandable question! Proving something has no effect under any possible condition is very hard. And we mention in our article that we cannot rule out a functional adaptation entirely. But because the larger fractal assemblies appear at non-physiological concentrations and
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@Bogdanul2
Well, we are pretty sure of that 😅 But these are very difficult to image. We show in the paper that the assembly principles definitely allow it and small angle Xray measurements show that they can grow in size beyond the three levels shown here.
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@BenjaminMallada
You should have seen our faces when we found out that there had been synthetic fractals designed just one floor below us 🤯😅
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@Dey_Gautam
Had the same thing happening to me - including the „almost dying“ part 🥲 and then learned about citrus trifoliata and i like actually how it looks now
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@_JoeMcKellar
If you still have the chance say hi to Laura from me (she was my awesome bachelor thesis supervisor) and to Georg! Otherwise I hope you had a great time there 😊
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@anthony_berndt
@ATinyGreenCell
I was so confused when i used one of these cyclers for the first time recently 🥲
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@PerezMedinaLu
Agreed, was already really hyped when i had the lysate! everything is more fun when you’re not only working with transparent solutions 😁
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