Large-scale analysis of posttranslational modifications in the hippocampus of patients with Alzheimer's disease using pI shift and label-free quantification without enrichment
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- Large-scale analysis of posttranslational modifications in the hippocampus of patients with Alzheimer's disease using pI shift and label-free quantification without enrichment
- Taewook Kang; Jae Ho Kim; Ingie Hong; Nanhyun Park; Helmut Heinsen; Joo-Yong Lee; Rivja Ravid; Isidro Ferrer; Jong Shin Yoo; Kyung-Hoon Kwon; Young Mok Park
- ANALYTICAL AND BIOANALYTICAL CHEMISTRY, v.406, no.22, pp.5433 - 5446
- SPRINGER HEIDELBERG
- Posttranslational modifications modulate protein
function in cells. Global analysis of multiple posttranslational
modifications can provide insight into physiology and disease,
but presents formidable challenges. In the present study, we
used a technique that does not require target enrichment to
analyze alterations in the phosphorylation and ubiquitination
of proteins from patients with Alzheimer’s disease (AD).
Guided by our previous findings, we applied three strategies
to further our understanding of the dysregulation of
posttranslationally modified proteins.We first identified phosphorylation
sites by determining peptide pI shifts using
OFFGEL. Second, using tandem mass spectrometry, we determined
the ubiquitination status of the proteins using an assay for a trypsin digestion remnant of ubiquitination (Gly-
Gly). Third, for large-scale discovery, we quantified the global
differences in protein expression. Of the proteins expressed in
AD tissue at levels of 2.0 or greater compared with controls,
60 were phosphorylated and 56 were ubiquitinated. Of the
proteins expressed at levels of 0.5 or lower compared with
controls, 81 were phosphorylated and 56 were ubiquitinated.
Approximately 98 % of the phosphopeptides exhibited a pI
shift.We identified 112 new phosphorylation sites (51.38 %),
and 92 new ubiquitination sites (96.84 %). Taken together, our
findings suggest that analysis of the alterations in
posttranslationally modified proteins may contribute to understanding
the pathogenesis of AD and other diseases.
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