Hyperphosphorylation of tau induces local polyproline II helix.
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 (3)J(alphaN) (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 alpha-helix. These results suggest that global reorganization of tau may occur upon hyperphosphorylation of proline-rich sequences in tau.
Bielska
Agata A
AA
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Zondlo
Neal J
NJ
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D006801:Humans; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D010769:Phosphothreonine / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D010455:Peptides; D016875:tau Proteins; D010769:Phosphothreonine; D010768:Phosphoserine; C011083:polyproline