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

Kaiser, Christoph J. O.; Peters, Carsten; Schmid, Philipp W. N.; Stavropoulou, Maria; Zou, Juan; Dahiya, Vinay; Mymrikov, Evgeny V.; Rockel, Beate; Asami, Sam; Haslbeck, Martin; Rappsilber, Juri; Reif, Bernd; Zacharias, Martin; Büchner, Johannes; Weinkauf, Sevil

doi:10.1038/s41594-019-0332-9

Cited by 46 publications

(67 citation statements)

References 87 publications

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“…Due to the high heterogeneity of the α-crystallin complex and, therefore, its inaccessibility in the crystalline form, EM methods have become the most successful ones in this field. The generally improved research tools, cryo-electron microscopy, and the enhanced computer processing of individual images have recently allowed to obtain the first models of both the authentic (natural) α-crystallin complex isolated from the bovine eye lens and the recombinant αB-crystallin complex [27,28,[36][37][38]. The studies of the αB-crystallin complex using negative staining in combination with computer processing of individual particles made it possible to improve the model of the αB-crystallin complex (resolution about 20 Å) [27,36,37].…”

Section: Discussionmentioning

confidence: 99%

“…The studies of the αB-crystallin complex using negative staining in combination with computer processing of individual particles made it possible to improve the model of the αB-crystallin complex (resolution about 20 Å) [27,36,37]. Nevertheless, little progress was achieved, except for the creation of one model [28], with highly heterogeneous authentic α-crystallin and αA-recombinant complexes [28,38]. So far, only the model of bovine α-crystallin complex has been proposed at the resolution of 44 Å.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, currently available is a model of the α-crystallin complex with a resolution of only about 44 Å [28], while no further attempts have been made to study the native structure owing to the high heterogeneity of the complex. Recently the different reduced models of αA-crystallin complexes were proposed [38]. The absence of a correct model complicates interpretation of the mechanism of chaperone activity of both native α-crystallin and αA-crystallin complexes.…”

Section: Introductionmentioning

confidence: 99%

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Structural and Functional Peculiarities of α-Crystallin

Selivanova

Galzitskaya

2020

Biology

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α-Crystallin is the major protein of the eye lens and a member of the family of small heat-shock proteins. Its concentration in the human eye lens is extremely high (about 450 mg/mL). Three-dimensional structure of native α-crystallin is unknown. First of all, this is the result of the highly heterogeneous nature of α-crystallin, which hampers obtaining it in a crystalline form. The modeling based on the electron microscopy (EM) analysis of α-crystallin preparations shows that the main population of the α-crystallin polydisperse complex is represented by oligomeric particles of rounded, slightly ellipsoidal shape with the diameter of about 13.5 nm. These complexes have molecular mass of about 700 kDa. In our opinion, the heterogeneity of the α-crystallin complex makes it impossible to obtain a reliable 3D model. In the literature, there is evidence of an enhanced chaperone function of α-crystallin during its dissociation into smaller components. This may indirectly indicate that the formation of heterogeneous complexes is probably necessary to preserve α-crystallin in a state inactive before stressful conditions. Then, not only the heterogeneity of the α-crystallin complex is an evolutionary adaptation that protects α-crystallin from crystallization but also the enhancement of the function of α-crystallin during its dissociation is also an evolutionary acquisition. An analysis of the literature on the study of α-crystallin in vitro led us to the assumption that, of the two α-crystallin isoforms (αA- and αB-crystallins), it is αA-crystallin that plays the role of a special chaperone for αB-crystallin. In addition, our data on X-ray diffraction analysis of α-crystallin at the sample concentration of about 170–190 mg/mL allowed us to assume that, at a high concentration, the eye lens α-crystallin can be in a gel-like stage. Finally, we conclude that, since all the accumulated data on structural-functional studies of α-crystallin were carried out under conditions far from native, they cannot adequately reflect the features of the functioning of α-crystallin in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural and Functional Peculiarities of α-Crystallin

Selivanova

Galzitskaya

2020

Biology

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“…The N-terminal region (NTR) (red), α-crystallin domain (ACD) (blue) and C-terminal region (CTR) (green) were highlighted for one of the dimers. Both NTRs have three helices, albeit they show different orientations [79,80]. (F) Hexameric subunit extracted from the pseudoatomic model of αB (PDB: 2YGD).…”

Section: The Structure Of Human Shspsmentioning

confidence: 99%

“…Interestingly, these pseudo-atomic models of recombinantly expressed αA and αB, generated by hybrid approaches combining structural data from cryo-electron microscopy (cryo-EM), NMR spectroscopy, small angle X-ray scattering (SAXS), and crosslinking-mass spectrometry (crosslinking-MS) together with molecular modelling simulations, indicate that the oligomers of the two sHsps are quite different in symmetry, dynamics and assembly organization [79,80,85,104].…”

Section: The Structure Of Human Shspsmentioning

confidence: 99%

Proteinaceous Transformers: Structural and Functional Variability of Human sHsps

Riedl¹,

Strauch²,

Catici³

et al. 2020

IJMS

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The proteostasis network allows organisms to support and regulate the life cycle of proteins. Especially regarding stress, molecular chaperones represent the main players within this network. Small heat shock proteins (sHsps) are a diverse family of ATP-independent molecular chaperones acting as the first line of defense in many stress situations. Thereby, the promiscuous interaction of sHsps with substrate proteins results in complexes from which the substrates can be refolded by ATP-dependent chaperones. Particularly in vertebrates, sHsps are linked to a broad variety of diseases and are needed to maintain the refractive index of the eye lens. A striking key characteristic of sHsps is their existence in ensembles of oligomers with varying numbers of subunits. The respective dynamics of these molecules allow the exchange of subunits and the formation of hetero-oligomers. Additionally, these dynamics are closely linked to the chaperone activity of sHsps. In current models a shift in the equilibrium of the sHsp ensemble allows regulation of the chaperone activity, whereby smaller oligomers are commonly the more active species. Different triggers reversibly change the oligomer equilibrium and regulate the activity of sHsps. However, a finite availability of high-resolution structures of sHsps still limits a detailed mechanistic understanding of their dynamics and the correlating recognition of substrate proteins. Here we summarize recent advances in understanding the structural and functional relationships of human sHsps with a focus on the eye-lens αA- and αB-crystallins.

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Peeking from behind the veil of enigma: emerging insights on small heat shock protein structure and function

Klevit

2020

Cell Stress and Chaperones

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This is a short paper on new ways to think about the structure and function of small heat shock proteins (sHSPs), perhaps the most enigmatic family among protein chaperones. The goal is to incorporate new observations regarding the disordered regions of small heat shock proteins (sHSPs) into the large body of structural information on the conserved structural alpha-crystallin domains (ACD) that define the sHSP family. Disordered regions (N-terminal region and C-terminal region or NTR and CTR, respectively) represent over 50% of the sHSP sequence space in the human genome and are refractory to traditional structural biology approaches, posing a roadblock on the path towards a mechanistic understanding of how sHSPs function. A model in which an ACD dimer serves as a template that presents three grooves into which other proteins or other segments of sHSPs can bind is presented. Short segments within the disordered regions are observed to bind into the ACD grooves. There are more binding segments than there are grooves, and each binding event is weak and transient, creating a dynamic equilibrium of tethered and untethered disordered regions. The ability of an NTR to be in dynamic equilibrium between tethered/sequestered and untethered states suggests several mechanistic alternatives that need not be mutually exclusive. New ways of thinking about (and approaching) the intrinsic properties of sHSPs may finally allow the veil of enigma to be removed from sHSPs.

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

Cited by 46 publications

References 87 publications

Structural and Functional Peculiarities of α-Crystallin

Structural and Functional Peculiarities of α-Crystallin

Proteinaceous Transformers: Structural and Functional Variability of Human sHsps

Peeking from behind the veil of enigma: emerging insights on small heat shock protein structure and function

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