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Nat Commun. 2019 Sep 11;10(1):4121. doi: 10.1038/s41467-019-12006-x.

The molecular basis of chaperone-mediated interleukin 23 assembly control.

Author information

1
Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany.
2
Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Zentrum München, Biedersteiner Str. 29, 80802, Munich, Germany.
3
Institute of Structural Biology, Helmholtz Center Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
4
Department of Bioengineering, Stanford University, 443 Via Ortega, Stanford, CA, 94305, USA.
5
Center for Integrated Protein Science Munich (CIPSM) at the Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85748, Garching, Germany. matthias.feige@tum.de.
6
Institute for Advanced Study, Technical University of Munich, Lichtenbergstr. 2a, 85748, Garching, Germany. matthias.feige@tum.de.

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.

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