Tissue transglutaminase modulates α-synuclein oligomerization


Segers-Nolten, Ine M.J. and Wilhelmus , Micha M.M. and Veldhuis, Gertjan and Rooijen, Bart D. van and Drukarch, Benjamin and Subramaniam, Vinod (2008) Tissue transglutaminase modulates α-synuclein oligomerization. Protein Science, 17 (8). pp. 1395-1402. ISSN 0961-8368

[img] PDF
Restricted to UT campus only
: Request a copy
Abstract:We have studied the interaction of the enzyme tissue transglutaminase (tTG), catalyzing cross-link formation between protein-bound glutamine residues and primary amines, with Parkinson's disease-associated α-synuclein protein variants at physiologically relevant concentrations. We have, for the first time, determined binding affinities of tTG for wild-type and mutant α-synucleins using surface plasmon resonance approaches, revealing high-affinity nanomolar equilibrium dissociation constants. Nanomolar tTG concentrations were sufficient for complete inhibition of fibrillization by effective α-synuclein cross-linking, resulting predominantly in intramolecularly cross-linked monomers accompanied by an oligomeric fraction. Since oligomeric species have a pathophysiological relevance we further investigated the properties of the tTG/α-synuclein oligomers. Atomic force microscopy revealed morphologically similar structures for oligomers from all α-synuclein variants; the extent of oligomer formation was found to correlate with tTG concentration. Unlike normal α-synuclein oligomers the resultant structures were extremely stable and resistant to GdnHCl and SDS. In contrast to normal β-sheet-containing oligomers, the tTG/α-synuclein oligomers appear to be unstructured and are unable to disrupt phospholipid vesicles. These data suggest that tTG binds equally effective to wild-type and disease mutant α-synuclein variants. We propose that tTG cross-linking imposes structural constraints on α-synuclein, preventing the assembly of structured oligomers required for disruption of membranes and for progression into fibrils. In general, cross-linking of amyloid forming proteins by tTG may prevent the progression into pathogenic species.
Item Type:Article
Copyright:© 2008 Wiley InterScience
Science and Technology (TNW)
Research Group:
Link to this item:http://purl.utwente.nl/publications/72349
Official URL:https://doi.org/10.1110/ps.036103.108
Export this item as:BibTeX
HTML Citation
Reference Manager


Repository Staff Only: item control page

Metis ID: 248984