Stepwise degradations and deamidation of the eye lens protein α-crystallin in ageing

Kleef, Frans S.M. van; Jong, Wilfried W. de; Hoenders, Herman J.

doi:10.1038/258264a0

Cited by 140 publications

(41 citation statements)

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“…While it is known that proline-directed kinases favour phosphorylation of Ser-Pro (Aitken et al, 1995) and similar cleavage patterns have been reported from both bovine and human αA-crystallin (Van Kleef et al, 1975;Takemoto, 1995), it is not known if this motif is recognized by proteases. A sequence pattern also emerges when looking at the penultimate two residues of the αA 66(67)(69)-80…”

Section: Discussionmentioning

confidence: 93%

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

McArthur

Aquilina

2010

Experimental Eye Research

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This article was originally published as Su, S.P., McArthur, J.D., Aquilina, J.A., Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach, Experimental Eye Research, 91(1), 2010, 97-103. Original item available here Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach AbstractLow molecular weight (LMW) peptides, derived from the breakdown of the major eye lens proteins, the crystallins, accumulate in the human lens with age. These LMW peptides are associated with age-related lens opacity and cataract, with some shown to inhibit the chaperone activity of α-crystallin. However, the mechanism(s) giving rise to the production of these peptides, as well as their distribution within the lens, are not well understood. In this study, we have mapped the distribution of these crystallin-derived peptides present in human lenses of different ages using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS). Our data showed that most of these LMW peptides emerge in the lens at early middle-age, with peptides greater than 1778 Da in mass being confined to the water insoluble fractions, and to a lesser extent the water soluble fractions of older lenses. MALDI-IMS analyses showed that four peptides, derived from αA-, αB-and γS crystallins, were confined to the lens nuclear fibre cells upon emergence during early middle-age, but were present in both the cortex and nucleus of old lenses. In contrast, another major peptide, derived from the C-terminal breakdown of βA3-crystallin, was present in the cortical and nuclear regions of both young and old lenses. A comparison between age-matched cataractous and non-cataractous lenses showed no distinct differences in LMW peptide profiles, indicating that although cataract may be a potential consequence caused by the emergence of these peptides, it does not contribute directly to the peptide-generating process. AbstractLow molecular weight (LMW) peptides, derived from the breakdown of the major eye lens proteins, the crystallins, accumulate in the human lens with age. These LMW peptides are associated with age-related lens opacity and cataract, with some shown to inhibit the chaperone activity of α-crystallin. However, the mechanism(s) giving rise to the production of these peptides, as well as their distribution within the lens, are not well understood. In this study, we have mapped the distribution of these crystallin-derived peptides present in human lenses of different ages using matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS).Our data showed that most of these LMW peptides emerge in the lens at early middle-age, with peptides greater than 1778 Da in mass being confined to the water insoluble fractions, and to a lesser extent the water soluble fractions of older lenses.MALDI-IMS analyses showed that four peptides, derived from αA-, αB-and γS-crystallins, were confined to t...

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Section: Discussionmentioning

confidence: 93%

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

McArthur

Aquilina

2010

Experimental Eye Research

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“…Within chaperones, deamidation of crystallin, a member of the Hsp27 family, occurs during aging and increases during cataract formation. 25,26 Interestingly, crystallin deamidation is in part catalyzed by tissue transglutaminase, an enzyme known to be involved in mouse MDB formation. 24,27 Notably, protein deamidation may lead to protein aggregation as noted for the spontaneous deamidation of the amylin peptide that induces the formation of amyloidlike aggregates.…”

Section: Discussionmentioning

confidence: 99%

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

Strnad¹,

Guo²,

So³

et al. 2008

Hepatology

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The cytoplasmic hepatocyte inclusions, Mallory-Denk bodies (MDBs), are characteristic of several liver disorders, including alcoholic and nonalcoholic steatohepatitis. In mice, MDBs can be induced by long-term feeding with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 3 to 4 months or rapidly reformed in DDC-induced then recovered mice by DDC refeeding or exposure to a wide range of toxins for only 5 to 7 days. The molecular basis for such a rapid reinduction of MDBs is unknown. We hypothesized that protein changes retained after DDC priming contribute to the rapid MDB reappearance and associate with MDB formation in general terms. Two-dimensional differential-in-gel-electrophoresis coupled with mass spectrometry were used to characterize protein changes in livers from the various treatment groups. The alterations were assessed by real-time reverse-transcription polymerase chain reaction and confirmed by immunoblotting. DDC treatment led to pronounced charged isoform changes in several chaperone families, including Hsp25, 60, 70, GRP58, GRP75, and GRP78, which lasted at least for 1 month after discontinuation of DDC feeding, whereas changes in other proteins normalized during recovery. DDC feeding also resulted in altered expression of Hsp72, GRP75, and Hsp25 and in functional impairment of Hsp60 and Hsp70 as determined using a protein complex formation and release assay. The priming toward rapid MDB reinduction lasts for at least 3 months after DDC discontinuation, but becomes weaker after prolonged recovery. MDB reinduction parallels the rapid increase in p62 and Hsp25 levels as well as keratin 8 cross-linking that is normally associated with MDB formation. Conclusion: Persistent posttranslational modifications in chaperone proteins, coupled with protein cross-linking and altered chaperone expression and function likely contribute to the "toxic memory" of DDC-primed mice. We hypothesize that similar changes are important contributors to inclusion body formation in several diseases. (HEPATOLOGY 2008;48:931-942.)

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“…Note that residues 117-120 of 16K are identical to the 4 C-terminal residues of B. * Marks the termini of major degradation products [17]. …”

Section: Figlcmentioning

confidence: 99%

“…cr-Crystallin extracted from bovine lens is extremely heterogeneous. Several major sites of proteolysis have been identified [15,17]. These are marked in figs 2 and 3.…”

Section: Febsletters February 1985mentioning

confidence: 99%

Domain structure and evolution in α‐crystallins and small heat‐shock proteins

Wistow

1985

FEBS Letters

164

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Stepwise degradations and deamidation of the eye lens protein α-crystallin in ageing

Cited by 140 publications

References 10 publications

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

Localization of low molecular weight crystallin peptides in the aging human lens using a MALDI mass spectrometry imaging approach

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

Domain structure and evolution in α‐crystallins and small heat‐shock proteins

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