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. [email protected].
  • 8. Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany. [email protected].
  • # 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.