We are thankful to our collaborators from the @spanglab.bsky.social and @maierlab.bsky.social @biozentrum.unibas.ch @unibas.ch

These condensates could revolutionize our understanding of protein folding and inspire new therapies for misfolding diseases like diabetes and cancer. A new era for targeting ER function! #Biomedicine #Therapeutics

Surprisingly, our findings reveal that PDIA6 multi-chaperone condensates are critical for insulin secretion by enhancing proinsulin folding, overturning decades-old models of insulin processing.

PDIA6 condensates recruit Hsp70 BiP, ERdj3, and Grp94 creating a functional hub for protein folding. The condensates dissolve upon ER stress but reform after stress relief, regulated by Ca²⁺ levels. This dynamic switch suggests a novel mechanism for maintaining ER homeostasis!

Our data reveal that calcium doesn’t affect the cycle, but combined with ADP accumulation it creates off-pathway states that prolong the nucleotide-bound lifetimes. This changes Hsp70’s function extending client protein interaction times — a new layer of cellular regulation!

This versatile in-cyclo NMR platform is adaptable to study diverse ATP-driven molecular machines beyond Hsp70 — enabling precise dissection of functional cycles, allosteric regulation, and the effect of cofactors or co-chaperones at unprecedented resolution.

Applied to the Hsp70 BiP NBD, in-cyclo NMR reveals all 11 microscopic kinetic rates of ATP binding, hydrolysis & product release — showing ADP·Pi release, not ATP hydrolysis, is the rate-limiting step of the cycle duration. Stay tuned for more results on the full-length Hsp70.