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The structure and oxidation of the eye lens chaperone ?A-crystallin.

ABSTRACT: The small heat shock protein ?A-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 ?A-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 ?A-crystallin heterogeneity. Human ?A-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 ?A-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 ?A-crystallin provides a basis for understanding its role in the eye lens.

SUBMITTER: Kaiser CJO

PROVIDER: S-EPMC7115824 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Kaiser Christoph J O CJO Peters Carsten C Schmid Philipp W N PWN Stavropoulou Maria M Zou Juan J Dahiya Vinay V Mymrikov Evgeny V EV Rockel Beate B Asami Sam S Haslbeck Martin M Rappsilber Juri J Reif Bernd B Zacharias Martin M Buchner Johannes J Weinkauf Sevil S

Nature structural & molecular biology 20191202 12

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 wh ...[more]

PMID: 31792453

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Project description:BackgroundThe teleost Astyanax mexicanus is a single species consisting of eyed surface-dwelling (surface fish) and blind cave-dwelling (cavefish) morphs. Cavefish eyes are lost through apoptosis of the lens, which in turn promotes the degeneration of other optic tissues. The αA-crystallin (αA-crys) gene is strongly downregulated in the cavefish lens and is located in a genomic region (QTL) responsible for eye loss. Therefore, αA-crys has been proposed as a candidate for regulating cavefish eye degeneration. The purpose of this study was to determine the mechanism of αA-crys downregulation and its role in cavefish eye degeneration.ResultsThe involvement of αA-crys in eye degeneration was confirmed by knocking down its expression in surface fish, which led to apoptosis of the lens. The underlying reason for αA-crys downregulation in cavefish was investigated by comparing genomic αA-crys DNA sequences in surface fish and cavefish, however, no obvious cis-regulatory factors were discovered. Furthermore, the cavefish αA-crys allele is expressed in surface fish x cavefish F1 hybrids, indicating that evolutionary changes in upstream genes are most likely responsible for αA-crys downregulation. In other species, Sox2 is one of the transcription factors that regulate lens crystallin genes during eye development. Determination of sox2 expression patterns during surface fish and cavefish development showed that sox2 is specifically downregulated in the cavefish lens. The upstream regulatory function of Sox2 was demonstrated by knockdown in surface fish, which abolished αA-crys expression and induced lens apoptosis.ConclusionsThe results suggest that αA-crys is required for normal eye development in cavefish via suppression of lens apoptosis. The regulatory changes involved in αA-crys downregulation in cavefish are in trans-acting factors rather than cis-acting mutations in the αA-crys gene. Therefore, αA-crys is unlikely to be the mutated gene(s) associated with an Astyanax eye QTL. The results reveal a genetic pathway leading from sox2 to αA-crys that is required for survival of the lens in Astyanax surface fish. Defects in this pathway may be involved in lens apoptosis and thus a cause of cavefish eye degeneration.

Dataset Information

The structure and oxidation of the eye lens chaperone ?A-crystallin.

Publications

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

Similar Datasets

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