The structure and oxidation of the eye lens chaperone αA-crystallin

Nat Struct Mol Biol. 2019 Dec;26(12):1141-1150. doi: 10.1038/s41594-019-0332-9.

Christoph J O Kaiser ^# ¹, Carsten Peters ^# ¹, Philipp W N Schmid ¹, Maria Stavropoulou ¹ ², Juan Zou ³, Vinay Dahiya ¹, Evgeny V Mymrikov ¹ ⁴, Beate Rockel ¹, Sam Asami ¹ ², Martin Haslbeck ¹, Juri Rappsilber ³ ⁵, Bernd Reif ¹ ², Martin Zacharias ⁶, Johannes Buchner ⁷, Sevil Weinkauf ⁸

Affiliations

1 Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany.
2 Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
3 Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, UK.
4 Institute for Biochemistry and Molecular Biology, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
5 Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
6 Center for Integrated Protein Science Munich at the Physics Department, Technische Universität München, Garching, Germany.
7 Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany. johannes.buchner@tum.de.
8 Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany. sevil.weinkauf@tum.de.
# Contributed equally.

PMID: 31792453 DOI: 10.1038/s41594-019-0332-9

Abstract

The small heat shock protein αA-crystallin is a molecular chaperone important for the optical properties of the vertebrate eye lens. It forms heterogeneous oligomeric ensembles. We determined the structures of human αA-crystallin oligomers by combining cryo-electron microscopy, cross-linking/mass spectrometry, NMR spectroscopy and molecular modeling. The different oligomers can be interconverted by the addition or subtraction of tetramers, leading to mainly 12-, 16- and 20-meric assemblies in which interactions between N-terminal regions are important. Cross-dimer domain-swapping of the C-terminal region is a determinant of αA-crystallin heterogeneity. Human αA-crystallin contains two cysteines, which can form an intramolecular disulfide in vivo. Oxidation in vitro requires conformational changes and oligomer dissociation. The oxidized oligomers, which are larger than reduced αA-crystallin and destabilized against unfolding, are active chaperones and can transfer the disulfide to destabilized substrate proteins. The insight into the structure and function of αA-crystallin provides a basis for understanding its role in the eye lens.

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