Mutations in Human αA-Crystallin/sHSP Affect Subunit Exchange Interaction with αB-Crystallin

Ilangovan, R.; Oonthonpan, Lalita; Abraham, E.C.

doi:10.1371/journal.pone.0031421

Cited by 13 publications

(7 citation statements)

References 32 publications

(39 reference statements)

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“…Co-immunoprecipitation confirmed the complexation and subunit exchange of WT αB-c and Hsp27 with R120G αB-c (Chavez Zobel et al 2003). Additionally, the rate of subunit exchange with various αA-c mutants and WT αB-c is slower compared to WT αA-c and αB-c (Raju et al 2012), implying that the subunit exchange is favoured between functional/non-mutant sHsps compared to their mutant/disease counterparts.…”

Section: Shsps Prevent Other Shsps From Misfolding and Aggregating Via Subunit Exchangementioning

confidence: 72%

The multifaceted nature of αB-crystallin

Hayashi

Carver

2020

Cell Stress and Chaperones

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In vivo, small heat-shock proteins (sHsps) are key players in maintaining a healthy proteome. αB-crystallin (αB-c) or HspB5 is one of the most widespread and populous of the ten human sHsps. Intracellularly, αB-c acts via its molecular chaperone action as the first line of defence in preventing target protein unfolding and aggregation under conditions of cellular stress. In this review, we explore how the structure of αB-c confers its function and interactions within its oligomeric self, with other sHsps, and with aggregation-prone target proteins. Firstly, the interaction between the two highly conserved regions of αB-c, the central αcrystallin domain and the C-terminal IXI motif and how this regulates αB-c chaperone activity are explored. Secondly, subunit exchange is rationalised as an integral structural and functional feature of αB-c. Thirdly, it is argued that monomeric αB-c may be its most chaperone-species active, but at the cost of increased hydrophobicity and instability. Fourthly, the reasons why heterooligomerisation of αB-c with other sHsps is important in regulating cellular proteostasis are examined. Finally, the interaction of αB-c with aggregation-prone, partially folded target proteins is discussed. Overall, this paper highlights the remarkably diverse capabilities of αB-c as a caretaker of the cell.

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Section: Shsps Prevent Other Shsps From Misfolding and Aggregating Via Subunit Exchangementioning

confidence: 72%

The multifaceted nature of αB-crystallin

Hayashi

Carver

2020

Cell Stress and Chaperones

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“…They have a great importance in maintaining the refraction index in the lens [16]. In the human lens three main classes of "crystallins" have been identified, i.e., α-crystallin -representing 40%, β-crystallin -about 35% and γ-crystallin -25% [5,17,18].…”

Section:  Discussionmentioning

confidence: 99%

Congenital cataract – clinical and morphological aspects

Tătaru

Costache³

et al. 2020

Rom J Morphol Embryol

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Congenital cataract is one of the main causes of blindness in newborns and children. According to the World Health Organization (WHO), there are about 14 million children suffering from congenital cataract. Our study is based on 82 children, males -46 (56.1%) and females -36 (43.9%), with congenital cataract operated in the same ophthalmological centre in Bucharest, Romania. Of the 82 patients, 49 (59.76%) had bilateral cataract and 33 (40.24%) unilateral cataract. Clinically, the most frequent was the total cataract, followed by lamellar, nuclear and cerulean. We employed nine surgical approaches in our patients, depending on the type of intraocular lens (IOL). Morphologically, obvious changes were rendered evident at the level of anterior and posterior capsules, as well as subcapsular.

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“…Assessment of the available surface hydrophobic patches of these mutant proteins showed a drastic increase in the surface hydrophobicity for R21W and R21L, while other mutants had lowered surface hydrophobicity as compared to the wild-type protein [63]. Another independent study revealed that the subunit exchange rates of these αA-crystallin mutants, R21W and R116C, with wild-type αB-crystallin decreased considerably as compared to when wild-type αA-crystallin interacted with wild-type αB-crystallin [64]. In summary, the drastic decrease in the chaperone function of R12C and R21W may be the consequence of: 1) reduction in subunit exchange rate with αB-crystallin; 2) alterations in the secondary, tertiary, and quaternary structures of the mutant proteins, which may be the critical factors behind the formation of congenital cataract.…”

Section: In Vitro Studies Associated With Arginine Mutations In Humentioning

confidence: 99%

“…In summary, the drastic decrease in the chaperone function of R12C and R21W may be the consequence of: 1) reduction in subunit exchange rate with αB-crystallin; 2) alterations in the secondary, tertiary, and quaternary structures of the mutant proteins, which may be the critical factors behind the formation of congenital cataract. Subunit exchange studies by Abraham’s group also revealed that both R54C and R49C mutations lowered the subunit exchange kinetics between αA- and αB-crystallin [64]. This decrease in subunit exchange rate and altered secondary structure due to these two mutations, may be a possible cause for cataract induction in the lens.…”

Section: In Vitro Studies Associated With Arginine Mutations In Humentioning

confidence: 99%

Differential role of arginine mutations on the structure and functions of α-crystallin

Panda¹,

Nandi²,

Chakraborty³

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background α-Crystallin is a major protein of the eye lens in vertebrates. It is composed of two subunits, αA- and αB-crystallin. α-Crystallin is an oligomeric protein having these two subunits in 3:1 ratio. It belongs to small heat shock protein family and exhibits molecular chaperone function, which plays an important role in maintaining the lens transparency. Apart from chaperone function, both subunits also exhibit anti-apoptotic property. Comparison of their primary sequences reveals that αA- and αB-crystallin posses 13 and 14 arginine residues, respectively. Several of them undergo mutations which eventually lead to various eye diseases such as congenital cataract, juvenile cataract, and retinal degeneration. Interestingly, many arginine residues of these subunits are modified during glycation and even some are truncated during aging. All these facts indicate the importance of arginine residues in α-crystallin. Scope of review In this review, we will emphasize the recent in vitro and in vivo findings related to congenital cataract causing arginine mutations in α-crystallin. Major conclusions Congenital cataract causing arginine mutations alters the structure and decreases the chaperone function of α-crystallin. These mutations also affect the lens morphology and phenotypes. Interestingly, non-natural arginine mutations (generated for mimicking the glycation and truncation environment) improve the chaperone function of α-crystallin which may play an important role in maintaining the eye lens transparency during aging. General significance The neutralization of positive charge on the guanidino group of arginine residues is not always detrimental to the functionality of α-crystallin.

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Mutations in Human αA-Crystallin/sHSP Affect Subunit Exchange Interaction with αB-Crystallin

Cited by 13 publications

References 32 publications

The multifaceted nature of αB-crystallin

The multifaceted nature of αB-crystallin

Congenital cataract – clinical and morphological aspects

Differential role of arginine mutations on the structure and functions of α-crystallin

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