The molecular basis of chaperone-mediated interleukin 23 assembly control

Susanne Meier, Sina Bohnacker, Carolin J. Klose, Abraham Lopez, Christian A. Choe, Philipp W. N. Schmid, Nicolas Bloemeke, Florian Rührnößl, Martin Haslbeck, Julia Esser- von Bieren, Michael Sattler, Po-Ssu Huang and Matthias J. Feige ()
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Susanne Meier: Technical University of Munich
Sina Bohnacker: Technical University of Munich
Carolin J. Klose: Technical University of Munich
Abraham Lopez: Technical University of Munich
Christian A. Choe: Stanford University
Philipp W. N. Schmid: Technical University of Munich
Nicolas Bloemeke: Technical University of Munich
Florian Rührnößl: Technical University of Munich
Martin Haslbeck: Technical University of Munich
Julia Esser- von Bieren: Technical University of Munich and Helmholtz Zentrum München
Michael Sattler: Technical University of Munich
Po-Ssu Huang: Stanford University
Matthias J. Feige: Technical University of Munich

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The functionality of most secreted proteins depends on their assembly into a defined quaternary structure. Despite this, it remains unclear how cells discriminate unassembled proteins en route to the native state from misfolded ones that need to be degraded. Here we show how chaperones can regulate and control assembly of heterodimeric proteins, using interleukin 23 (IL-23) as a model. We find that the IL-23 α-subunit remains partially unstructured until assembly with its β-subunit occurs and identify a major site of incomplete folding. Incomplete folding is recognized by different chaperones along the secretory pathway, realizing reliable assembly control by sequential checkpoints. Structural optimization of the chaperone recognition site allows it to bypass quality control checkpoints and provides a secretion-competent IL-23α subunit, which can still form functional heterodimeric IL-23. Thus, locally-restricted incomplete folding within single-domain proteins can be used to regulate and control their assembly.

Date: 2019
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DOI: 10.1038/s41467-019-12006-x

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