2007 Fiscal Year Final Research Report Summary
Investigation of transglutaminase-induced structural change of proteins related to degenerative diseases
| Project/Area Number |
18570150
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biophysics
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| Research Institution | University of Fukui |
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Principal Investigator |
KONNO Takashi University of Fukui, Faculty of Medical Sciences, Associate Professor (50225637)
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| Project Period (FY) |
2006 – 2007
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| Keywords | transglutaminase / enzymatic modification / degenerative diseases / protein aggregation / amvloid / tau protein |
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| Research Abstract |
A variety of protein species are involved in pathogenesis of human degenerative diseases such as Alzheimer's and prion diseases. These protein molecules are targets of pathologically relevant biochemical modifications including transglutaminase-catalyzed modification (TG modification), which induce quite complex molecular processes in the patients' bodies. During the research period, our study mainly focused the events related to amyloidgenic proteins. We have investigated molecular mechanisms of biochemical effects upon the amyloid formation such as those by TG modification and phosphorylation. For detailed studies, amyloidgenic short peptides derived from pathogenic proteins were synthesized with or without the biochemical modifications, and their molecular structures and aggregation properties were analyzed by many spectroscopic and microscopic methods. The results of our experimental studies include:
1. Amyloid formations of polyglutamine peptides and tau-derived core peptides were
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strongly inhibited by the TG modification. Several different molecular mechanisms, such as direct introduction of negative charges on the peptide sequence or cross-linking with polyamines, plausibly caused the inhibition effects.
2. Amyloid formation of the tau-derived peptides was also influenced by phosphorylation very efficiently, mainly by introduction of negative charges of the phosphate group and their interactions with the neighboring charged residues. The effects depended strongly upon the position of the phosphorylation site. We have also found that a trace amount of phosphorylated molecules can alter the aggregation propensity of the whole system.
During the studies above, we also found that the effects of the biochemical modifications depended strongly upon environmental factors. For getting deeper insights into environmental effects upon the biochemically modified amyloid formation, we investigated non-linearly complex environmental effects upon amyloidgenesis. Additionally, for future extension of the present analysis, we also performed some methodological studies using chemically modified membrane proteins. Less
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