Alpha-crystallin-derived peptides as therapeutic chaperones

Raju, Murugesan; Santhoshkumar, Puttur; Sharma, K. Krishna

doi:10.1016/j.bbagen.2015.06.010

Cited by 34 publications

(26 citation statements)

References 81 publications

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“…Certain crystallin fragments also affected α-crystallin chaperone activity, and suppressed aggregation of proteins [20] . Further, the mini-chaperones derived from α-crystallin chaperone region suppressed the aggregation of proteins, block ed amyloid fibril formation, stabilized mutant proteins, sequester metal ions, and exhibit anti-apoptotic properties [20] . Together, the above reports suggest a potential role of crystallin fragments in aggregation and cross-linking in vivo, and also as therapeutic chaperones.…”

Section: Introductionmentioning

confidence: 99%

Post-translationally modified human lens crystallin fragments show aggregation in vitro

Srivastava

Chaves

et al. 2017

Biochemistry and Biophysics Reports

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BackgroundCrystallin fragments are known to aggregate and cross-link that lead to cataract development. This study has been focused on determination of post-translational modifications (PTMs) of human lens crystallin fragments, and their aggregation properties.MethodsFour crystallin fragments-containing fractions (Fraction I [∼3.5 kDa species], Fraction II [∼3.5–7 kDa species], Fraction III [∼7–10 kDa species] and Fraction IV [>10–18 kDa species]), and water soluble high molecular weight (WS-HMW) protein fraction were isolated from water soluble (WS) protein fraction of human lenses of 50–70 year old-donors. The crystallin fragments of the Fractions I–IV were separated by two-dimensional (2D)-gel electrophoresis followed by analysis of their gel-spots by mass spectrometry. The Fractions I–IV were examined for their molecular mass, particle-diameters, amyloid fibril formation, and for their aggregation by themselves and with WS-HMW proteins.ResultsCrystallin fragments in Fractions I–IV were derived from α-, β- and γ-crystallins, and their 2D-gel separated spots contained multiple crystallins with PTMs such as oxidation, deamidation, methylation and acetylation. Crystallin fragments from all the four fractions exhibited self-aggregated complexes ranging in Mr from 5.5×105 to 1.0×108 Da, with diameters of 10–28 nm, and amyloid fibril-like formation, and aggregation with WS-HMW proteins.ConclusionThe crystallin fragments exhibited several PTMs, and were capable of forming aggregated species by themselves and with WS-HMW proteins, suggesting their potential role in aggregation process during cataract development.General significanceCrystallin fragments play a major role in human cataract development.

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Section: Introductionmentioning

confidence: 99%

Post-translationally modified human lens crystallin fragments show aggregation in vitro

Srivastava

Chaves

et al. 2017

Biochemistry and Biophysics Reports

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“…The peptide has been named 'mini-chaperone' by Sharma and co-workers. In addition, F71-K88 αAc forms amyloid fibrils (Raju et al 2016;Tanaka et al 2008). However, addition of the last ten amino acids of αAc, i.e.…”

Section: Introductionmentioning

confidence: 99%

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Carver

Grosas

Ecroyd

et al. 2017

Cell Stress and Chaperones

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Small heat-shock proteins (sHsps), such as αB-crystallin, are one of the major classes of molecular chaperone proteins. In vivo, under conditions of cellular stress, sHsps are the principal defence proteins that prevent large-scale protein aggregation. Progress in determining the structure of sHsps has been significant recently, particularly in relation to the conserved, central and β-sheet structured α-crystallin domain (ACD). However, an understanding of the structure and functional roles of the N-and C-terminal flanking regions has proved elusive mainly because of their unstructured and dynamic nature. In this paper, we propose functional roles for both flanking regions, based around three properties: (i) they act in a localised crowding manner to regulate interactions with target proteins during chaperone action, (ii) they protect the ACD from deleterious amyloid fibril formation and (iii) the flexibility of these regions, particularly at the extreme C-terminus in mammalian sHsps, provides solubility for sHsps under chaperone and nonchaperone conditions. In the eye lens, these properties are highly relevant as the crystallin proteins, in particular the two sHsps αA-and αB-crystallin, are present at very high concentrations.

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“…Our proteomics data showed decreased expression of several crystallin proteins (CRYAA, CRYAB, and CRYBB2) in Ambra1 +/gt retinae. Alpha-crystallins display chaperone like features, belong to the small heat shock family 77 and can protect cells from stress induced apoptosis 78 . Alpha-crystallin expression in the retina is increased in various stress conditions such as diabetic retinopathy or glaucoma, aiming to protect the retinal cells from cell death 4,79 .…”

Section: Discussionmentioning

confidence: 99%

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

et al. 2020

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Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d Ambra1 +/gt (autophagy/beclin-1 regulator 1 +/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+ , an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors.

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Alpha-crystallin-derived peptides as therapeutic chaperones

Cited by 34 publications

References 81 publications

Post-translationally modified human lens crystallin fragments show aggregation in vitro

Post-translationally modified human lens crystallin fragments show aggregation in vitro

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

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