title: Tissue transglutaminase-mediated glutamine deamidation of beta-amyloid peptide increases peptide solubility, whereas enzymatic cross-linking and peptide fragmentation may serve as molecular triggers for rapid peptide aggregation.
abstract: Tissue transglutaminase (TGase) has been implicated in a number of cellular processes and disease states, where the enzymatic actions of TGase may serve in both, cell survival and apoptosis. To date, the precise functional properties of TGase in cell survival or cell death mechanisms still remain elusive. TGase-mediated cross-linking has been reported to account for the formation of insoluble lesions in conformational diseases. We report here that TGase induces intramolecular cross-linking of β-amyloid peptide (Aβ), resulting in structural changes of monomeric Aβ. Using high resolution mass spectrometry (MS) of cross-linked Aβ peptides, we observed a shift in mass, which is, presumably associated with the loss of NH3 due to enzymatic transamidation activity and hence intramolecular peptide cross-linking. We have observed that a large population of Aβ monomers contained an 0.984 Da increase in mass at a glutamine residue, indicating that glutamine 15 serves as an indispensable substrate in TGase-mediated deamidation to glutamate 15. We provide strong analytical evidence on TGase-mediated Aβ peptide dimerization, through covalent intermolecular cross-linking and hence the formation of Aβ1-40 dimers. Our in depth analyses indicate that TGase-induced post-translational modifications of Aβ peptide may serve as an important seed for aggregation.
authors.affiliation: Proteomics Core Facility, AI 0151, Station 15, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland. adrien.schmid@epfl.ch
authors.forename: Adrien W
authors.initials: AW
authors.lastname: Schmid
authors.forename: Enrico
authors.initials: E
authors.lastname: Condemi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Tuchscherer
authors.forename: Diego
authors.initials: D
authors.lastname: Chiappe
authors.forename: Manfred
authors.initials: M
authors.lastname: Mutter
authors.forename: Horst
authors.initials: H
authors.lastname: Vogel
authors.forename: Marc
authors.initials: M
authors.lastname: Moniatte
authors.forename: Yury O
authors.initials: YO
authors.lastname: Tsybin
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002853:Chromatography, Liquid; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D007525:Isoelectric Focusing; D046529:Microscopy, Electron, Transmission; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D011503:Transglutaminases