Interactions between A? and mutated Tau lead to polymorphism and induce aggregation of A?-mutated tau oligomeric complexes.

ABSTRACT: One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the ?K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-à-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer's disease A? peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between A? and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between A? and mutated tau, we constructed fourteen ?K280 mutated tau-A?17-42 oligomeric complexes. In seven of the mutated tau-A?17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-A?17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and A? oligomers: interactions of one monomer of the A? oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire A? oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of A? trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of A? and mutated tau oligomers, polymorphic mutated tau-A?17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. A? trimers alternating with mutated tau trimers constituted a structurally stable confined ?-structure, albeit one that was energetically less stable than all the other constructed models.

SUBMITTER: Raz Y 

PROVIDER: S-EPMC3741189 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature