Age‐dependent deamidation of glutamine residues in human γS crystallin: Deamidation and unstructured regions

Hooi, Michelle; Raftery, Mark J.; Truscott, Roger J.W.

doi:10.1002/pro.2095

Cited by 37 publications

(36 citation statements)

References 40 publications

(72 reference statements)

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“…Using high-resolution mass spectrometry and software that automatically extracted and matched chromatographic peaks for peptides between 2D LC/MS runs, they found no generalized increase in deamidation in cataractous versus normal lenses. Similar results were also reported in a study of deamidation at Gln 92 and Gln170 residues in γ S-crystallin (Hooi et al, 2012a). This is in contrast to other researchers who have reported specific sites of deamidation that are increased in cataractous lenses (Hooi et al, 2012b; Lapko et al, 2002; Takemoto and Boyle, 1999, 2000; Takemoto et al, 1990).…”

Section: Deamidation In Aged Human Lenssupporting

confidence: 90%

“…Crystallins are extensively modified during normal aging and cataracts (Hains and Truscott, 2007, 2010; Harrington et al, 2004; Hooi et al, 2012a; Lampi et al, 1998; Lund et al, 1996; Ma et al, 1998; Miesbauer et al, 1994; Srivastava and Srivastava, 2003; Takemoto, 1998b; Wilmarth et al, 2006; Zhang et al, 2003). The use of mass spectrometry has unambiguously identified deamidation as the cause for the increase in acidic crystallins in early reports from the human lens (de Jong et al, 1988; Groenen et al, 1990; Van Kleef et al, 1975; Voorter et al, 1988, 1987).…”

Section: Deamidation In Aged Human Lensmentioning

confidence: 99%

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Lens β-crystallins: The role of deamidation and related modifications in aging and cataract

Lampi¹,

Wilmarth²,

Murray³

et al. 2014

Progress in Biophysics and Molecular Biology

126

117

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Crystallins are the major proteins in the lens of the eye and function to maintain transparency of the lens. Of the human crystallins, α, β, and γ, the β-crystallins remain the most elusive in their structural significance due to their greater number of subunits and possible oligomer formations. The β-crystallins are also heavily modified during aging. This review focuses on the functional significance of deamidation and the related modifications of racemization and isomerization, the major modifications in β-crystallins of the aged human lens. Elucidating the role of these modifications in cataract formation has been slow, because they are analytically among the most difficult post-translational modifications to study. Recent results suggest that many amides deamidate to similar extent in normal aged and cataractous lenses, while others may undergo greater deamidation in cataract. Mimicking deamidation at critical structural regions induces structural changes that disrupt the stability of the β-crystallins and lead to their aggregation in vitro. Deamidations at the surface disrupt interactions with other crystallins. Additionally, the α-crystallin chaperone is unable to completely prevent deamidated β-crystallins from insolubilization. Therefore, deamidation of β-crystallins may enhance their precipitation and light scattering in vivo contributing to cataract formation. Future experiments are needed to quantify differences in deamidation rates at all Asn and Gln residues within crystallins from aged and cataractous lenses, as well as racemization and isomerization which potentially perturb protein structure greater than deamidation alone. Quantitative data is greatly needed to investigate the importance of these major age-related modifications in cataract formation.

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Section: Deamidation In Aged Human Lenssupporting

confidence: 90%

Section: Deamidation In Aged Human Lensmentioning

confidence: 99%

Lens β-crystallins: The role of deamidation and related modifications in aging and cataract

Lampi¹,

Wilmarth²,

Murray³

et al. 2014

Progress in Biophysics and Molecular Biology

126

117

View full text Add to dashboard Cite

show abstract

“…Once the major sites of deamidation/isomerization obtained from proteomic experiments were mapped onto the structures, a consistent picture emerged. Sites of racemization and deamidation were localized almost exclusively within unstructured regions [24, 30]. This finding is consistent with other data [31, 32].…”

Section: Spontaneous Ptms Occur In Unstructured Regions Within Proteinssupporting

confidence: 91%

“…Deamidation of Asn and Gln has been widely studied [24–26]. Asn deamidates more readily than Gln [27].…”

Section: Deamidationmentioning

confidence: 99%

The etiology of human age-related cataract. Proteins don't last forever

Truscott

Friedrich

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

101

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Background It is probable that the great majority of human cataract results from the spontaneous decomposition of long-lived macromolecules in the human lens. Breakdown/reaction of long-lived proteins is of primary importance and recent proteomic analysis has enabled the identification of the particular crystallins, and their exact sites of amino acid modification. Scope of review Analysis of proteins from cataractous lenses revealed that there are sites on some structural proteins that show a consistently greater degree of deterioration than age-matched normal lenses. Major conclusions The most abundant posttranslational modification of aged lens proteins is racemization. Deamidation, truncation and crosslinking, each arising from the spontaneous breakdown of susceptible amino acids within proteins, are also present. Fundamental to an understanding of nuclear cataract etiology, it is proposed that once a certain degree of modification at key sites occurs, that protein-protein interactions are disrupted and lens opacification ensues. General Significance Since long-lived proteins are now recognized to be present in many other sites of the body, such as the brain, the information gleaned from detailed analyses of degraded proteins from aged lenses will apply more widely to other age-related human diseases.

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“…Some amino acids within LLPs change in characteristic ways to yield stable products, “signatures” that can be assayed using proteomic techniques [21, 22]. The details of these changes and their functional consequences will be discussed in more detail later in this article.…”

Section: How Do We Know That Proteins Are Long-lived?mentioning

confidence: 99%

Old Proteins in Man: A Field in its Infancy

Truscott

Schey

Friedrich

2016

Trends in Biochemical Sciences

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It has only recently been appreciated that the human body contains many long-lived proteins. Their gradual degradation over time contributes to human aging and probably also to a range of age-related disorders. Indeed progressive damage of proteins may be implicated in the fact that many neurological diseases do not appear until after middle age. A major factor responsible for the deterioration of old proteins is the spontaneous breakdown of susceptible amino acid residues resulting in racemisation, truncation, deamidation, and cross-linking. When proteins decompose in this way, their structures and functions may be altered and novel epitopes can be formed that can induce an autoimmune response.

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Age‐dependent deamidation of glutamine residues in human γS crystallin: Deamidation and unstructured regions

Cited by 37 publications

References 40 publications

Lens β-crystallins: The role of deamidation and related modifications in aging and cataract

Lens β-crystallins: The role of deamidation and related modifications in aging and cataract

The etiology of human age-related cataract. Proteins don't last forever

Old Proteins in Man: A Field in its Infancy

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