Carolin Klose

Huge thanks to all co-authors at @tum.de and @mpibiochem.bsky.social for making this work possible!
#ERliterature #chaperone #proteostasis
9/9

So what happens after binding?
We found that challenging TMDs remain bound to EMC and are ER-retained—but once a partner for productive assembly is available, EMC binding is reduced and the protein can exit the ER.
8/9

Molecular dynamics simulations explain this: Polar residues induce a tilted orientation of the TMD in the bilayer. EMC binding stabilizes them in an upright pose, likely facilitating proper folding and assembly.
7/9

But how does EMC recognize them?
Surprisingly, mutational analysis and site-specific crosslinking showed that EMC doesn't bind the polar face of the TMD—but engages the opposite, hydrophobic side.
6/9

Why these clients?
Their TMDs often contain polar/charged residues needed for function but are only marginally stable in the membrane—making them ideal candidates for chaperone support during folding and assembly.
5/9

How does this translate to natural proteins?
We trained and validated a neural network (ipredEMC) to predict EMC binding proteome-wide. This tool revealed that transporters and ion channels are major chaperone clients.
4/9

To understand what drives EMC binding, we turned to a minimal model system. Using a single-pass model transmembrane domain (TMD) and systematic residue substitutions, we found that mostly polar and charged residues within the TMD enhace EMC binding.
3/9

Using site-specific photocrosslinking and mass spectrometry, we mapped interactions at the lipid-filled cavity of the EMC, revealing a broad spectrum of membrane proteins extending far beyond known insertase clients.
2/9

The EMC acts as a chaperone for membrane proteins - Nature Communications Membrane proteins are essential for any cell but difficult to fold. Here, the authors show that the EMC acts as a chaperone for membrane proteins. They dissect client recognition and provide a molecul...

Excited to share our latest study in @natcomms.nature.com , where we characterize the chaperone function of the ER membrane protein complex (EMC)—supporting membrane protein biogenesis beyond insertion!
1/9

www.nature.com/articles/s41...

Congratulations Leo! 🥳

Wow, that's amazing! Congratulations!