Herling, Therese W; Cassaignau, Anaïs ME; Wentink, Anne S; Peter, Quentin AE; Kumar, Pavan C; Kartanas, Tadas; Schneider, Matthias M; ... Knowles, Tuomas PJ; + view all Herling, Therese W; Cassaignau, Anaïs ME; Wentink, Anne S; Peter, Quentin AE; Kumar, Pavan C; Kartanas, Tadas; Schneider, Matthias M; Cabrita, Lisa D; Christodoulou, John; Knowles, Tuomas PJ; - view fewer (2024) Thermodynamic profiles for cotranslational trigger factor substrate recognition. Science Advances , 10 (28) , Article eadn4824. 10.1126/sciadv.adn4824.

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Abstract

Molecular chaperones are central to the maintenance of proteostasis in living cells. A key member of this protein family is trigger factor (TF), which acts throughout the protein life cycle and has a ubiquitous role as the first chaperone encountered by proteins during synthesis. However, our understanding of how TF achieves favorable interactions with such a diverse substrate base remains limited. Here, we use microfluidics to reveal the thermodynamic determinants of this process. We find that TF binding to empty 70S ribosomes is enthalpy-driven, with micromolar affinity, while nanomolar affinity is achieved through a favorable entropic contribution for both intrinsically disordered and folding-competent nascent chains. These findings suggest a general mechanism for cotranslational TF function, which relies on occupation of the exposed TF-substrate binding groove rather than specific complementarity between chaperone and nascent chain. These insights add to our wider understanding of how proteins can achieve broad substrate specificity.

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