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Published online before print May 27, 2008, 10.1110/ps.036103.108
Protein Science (2008), 17:1395-1402. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Tissue transglutaminase modulates {alpha}-synuclein oligomerization

Ine M.J. Segers-Nolten1, Micha M.M. Wilhelmus2, Gertjan Veldhuis1, Bart D. van Rooijen1, Benjamin Drukarch2, and Vinod Subramaniam1

1 Biophysical Engineering Group, MESA+ Institute for Nanotechnology and Institute for Biomedical Technology, University of Twente, 7500 AE Enschede, The Netherlands
2 Department of Anatomy and Neurosciences, Institute for Clinical and Experimental Neurosciences (ICEN), VU University Medical Center, Amsterdam, The Netherlands

(RECEIVED April 29, 2008; FINAL REVISION May 22, 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 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/{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 effective to wild-type and disease mutant {alpha}-synuclein variants. We propose that tTG cross-linking imposes structural constraints on {alpha}-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.

Keywords: {alpha}-synuclein; tissue transglutaminase; cross-linking; oligomer; surface plasmon resonance; atomic force microscopy; Parkinson's disease


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