Web Release Date: April 5,
Hyperphosphorylation of Tau Induces Local Polyproline II Helix
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716
Received December 31, 2005
Revised Manuscript Received February 27, 2006
Abstract:
Alzheimer's disease is characterized by two protein precipitates, extracellular amyloid plaques
and intracellular neurofibrillary tangles (NFTs). The primary constituent of NFTs is a hyperphosphorylated
form of the microtubule-binding protein tau. Hyperphosphorylation of tau on over 30 residues, primarily
within proline-rich sequences, is associated with conformational changes whose nature is poorly defined.
Peptides derived from the proline-rich region of tau (residues 174-242) were synthesized, and the
conformations were analyzed for the nonphosphorylated and phosphorylated peptides. CD and NMR data
indicate that phosphorylation of serine and threonine residues in proline-rich sequences induces a
conformational change to a type II polyproline helix. The largest phosphorylation-dependent conformational
changes observed by CD were for tau peptides incorporating residues 174-183 or residues 229-238.
Phosphoserine and phosphothreonine residues exhibited ordered values of 3J
N (3.1-6.2 Hz; mean = 4.7
Hz) compared to nonphosphorylated serine and threonine. Phosphorylation of a tau peptide consisting of
tau residues 196-209 resulted in the disruption of a nascent -helix. These results suggest that global
reorganization of tau may occur upon hyperphosphorylation of proline-rich sequences in tau.
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