Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to microtubules.
Aggregation of the microtubule-associated protein tau into neurofibrillary tangles is the pathological hallmark of a variety of dementias. For reasons not yet known, tau becomes excessively phosphorylated in Alzheimer's brains and as a result no longer binds properly to microtubules. Here we studied the impact of phosphorylation on the conformational and binding properties of the repeat region of tau (K18) that is necessary for microtubule assembly and forms the core of paired helical filaments. To mimic phosphorylation, we introduced four mutations of serine to glutamate residues at positions 262, 293, 324, and 356. NMR spectroscopy demonstrates that pseudophosphorylation at these sites modifies the structural properties in repeats 1 and 2, in particular for Gln265-Lys267. Gln265-Lys267 are in close proximity to Ser262, the phosphorylation site that most strongly attenuates binding to microtubules. In contrast, the pseudophosphorylation mimic of tau efficiently interacts with the polyanion heparin. Thus, phosphorylation of the repeat region of natively unfolded tau induces specific conformational changes that have a strong impact on its biological function and involvement in disease.
Fischer
Daniela
D
Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.
Mukrasch
Marco D
MD
Biernat
Jacek
J
Bibow
Stefan
S
Blackledge
Martin
M
Griesinger
Christian
C
Mandelkow
Eckhard
E
Zweckstetter
Markus
M
D000544:Alzheimer Disease / Q000378:metabolism; D001665:Binding Sites; D002942:Circular Dichroism; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D011487:Protein Conformation; D012694:Serine / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
D016875:tau Proteins; D018698:Glutamic Acid; D012694:Serine