Synthesis and conformational properties of phosphopeptides related to the human tau protein.
In the brains of Alzheimer's disease patients, the tau protein dissociates from the axonal microtubule and abnormally aggregates to form a paired helical filament (PHF). One of the priorities in Alzheimer research is to determine the effects of abnormal phosphorylation on the local structure. A series of peptides corresponding to isolated regions of tau protein have been successfully synthesized using Fmoc-based chemistry and their conformations were determined by 1H NMR spectroscopy and circular dichroism (CD) spectroscopy. Immunodominant peptides corresponding to tau-(256-273), tau-(350-367) and two phosphorylated derivatives in which a single Ser was phosphorylated at positions 262 and 356, respectively, were the main focus of the study. A direct alteration of the local structure after phosphorylation constitutes a new strategy through which control of biological activity can be enforced. In our study on Ser262 in R1 peptide and Ser356 in R4 peptide, phosphorylation modifies both the negative charge and the local conformation nearby the phosphorylation sites. Together, these structural changes indicate that phosphorylation may act as a conformational switch in the binding domain of tau protein to alter specificity and affinity of binding to microtubule, particularly in response to the abnormal phosphorylation events associated with Alzheimer's disease.
Du
Jin-Tang
JT
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
Li
Yan-Mei
YM
Ma
Qing-Feng
QF
Qiang
Wei
W
Zhao
Yu-Fen
YF
Abe
Hiroshi
H
Kanazawa
Kenji
K
Qin
Xu-Rong
XR
Aoyagi
Ryousuke
R
Ishizuka
Yasuko
Y
Nemoto
Tadashi
T
Nakanishi
Hiroshi
H
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D002942:Circular Dichroism; D006801:Humans; D007477:Ions; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010748:Phosphopeptides / Q000737:chemistry*; D010766:Phosphorylation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011522:Protons; D012694:Serine / Q000737:chemistry; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
D007477:Ions; D010455:Peptides; D010748:Phosphopeptides; D011522:Protons; D016875:tau Proteins; D012694:Serine