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Published online before print May 27, 2008
Protein Science, DOI: 10.1110/ps.036103.108
 Copyright © 2008 The Protein Society
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Tissue transglutaminase modulates {alpha}-synuclein oligomerization

Ine Segers-Nolten1, Micha Wilhelmus2, Gertjan Veldhuis1, Bart van Rooijen1, Benjamin Drukarch2, and Vinod Subramaniam1,3

1 University of Twente;
2 VU University Medical Center

(RECEIVED April 29, 2008; ACCEPTED May 22, 2008)

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 {alpha}-synuclein protein variants at physiologically relevant concentrations. We have, for the first time, determined binding affinities of tTG for wild-type and mutant {alpha}-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 {alpha}-synuclein crosslinking, resulting predominantly in intramolecularly crosslinked monomers accompanied by an oligomeric fraction. Since oligomeric species have a pathophysiological relevance we further investigated the properties of the tTG/{alpha}-synuclein oligomers. Atomic force microscopy revealed morphologically similar structures for oligomers from all {alpha}-synuclein variants; the extent of oligomer formation was found to correlate with tTG concentration. Unlike normal {alpha}-synuclein oligomers the resultant structures were extremely stable and resistant to GdnHCl and SDS. In contrast to normal β-sheet containing oligomers, the tTG/{alpha}-synuclein oligomers appear to be unstructured and are unable to disrupt phospholipid vesicles. These data suggest that tTG binds equally effectively to wild-type and disease mutant {alpha}-synuclein variants. We propose that tTG crosslinking imposes structural constraints on {alpha}-synuclein preventing the assembly of structured oligomers required for disruption of membranes and for progression into fibrils. In general, crosslinking of amyloid forming proteins by tTG may prevent the progression into pathogenic species.

Keywords: alpha-synuclein; atomic force microscopy; crosslinking; oligomer; surface plasmon resonance; tissue transglutaminase

3 E-mail: v.subramaniam{at}tnw.utwente.nl


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