Two different types of physical bonding have been proposed to involve in the formation of neuronal inclusions of patients with neurodegenerative diseases such as Alzheimer's, Parkinson's, and polyglutamine diseases. One is the noncovalent bonding that stabilizes the amyloid-type fibrous aggregates, and the other is the covalent cross-linking catalyzed by tissue transglutaminase. The cross-linking is subdivided into the inter- and intramolecular cross-linking. Little attention has been paid to the pathological roles of the intramolecular cross-linking. To elucidate the possible interplay between the intramolecular cross-linking and the amyloid-type fibril formation, we performed an in vitro aggregation analysis of three intracellular amyloidgenic proteins (a domain of tau protein, alpha-synuclein, and truncated yeast prion Sup35) in the presence of tissue transglutaminase. The analysis was performed in low concentrations of the proteins using techniques including thioflavin T binding and mass spectrometry. The results demonstrated that the amyloid-type fibril formation was strongly inhibited by the transglutaminase-catalyzed intramolecular cross-linking, which blocked both the nucleation and the fiber extension steps of the amyloid formation. Far-UV CD spectroscopy indicated that the cross-linking slightly altered the backbone conformation of the proteins. It is likely that conformational restriction imposed by the intramolecular cross-links has impaired the ordered assembly of the amyloidgenic proteins. Nonamyloid type aggregation was also suppressed by the intramolecular cross-links. On the basis of the results, we proposed that tissue transglutaminase is a modulator for the protein aggregation and can act defensively against the fibril deposition in neurons.
We previously repoted that amyloid formation of Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide is strongly modified by soluble proteins with electrostatic interactions. An extension of this study was done for providing further insights into interactions between amyloidgenic and other soluble proteins, partly motivated by the question whether the interaction is observed for more pathologically important cases. The results gave some general aspects of the interaction by demonstrating several different modes of the interactions. It was, for example, indicated that distinction between specific and non-specific modes of the interactions are rather ambiguous, and some more important suggestions were also obtained.
1P014タイワンカブトムシ由来セリンプロテアーゼ阻害タンパク質 オリクチンの変異体とトリプシンの複合体の構造解析 Crystal structure of the M14R mutant of oryctin, a Kazal-type serine protease inhibitor, in complex with trypsin
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