title: Synthesis and conformational properties of phosphopeptides related to the human tau protein.
abstract: 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.
authors.affiliation: Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
authors.forename: Jin-Tang
authors.initials: JT
authors.lastname: Du
authors.forename: Yan-Mei
authors.initials: YM
authors.lastname: Li
authors.forename: Qing-Feng
authors.initials: QF
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.forename: Yu-Fen
authors.initials: YF
authors.lastname: Zhao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Kenji
authors.initials: K
authors.lastname: Kanazawa
authors.forename: Xu-Rong
authors.initials: XR
authors.lastname: Qin
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Aoyagi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ishizuka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nemoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
mesh_terms: 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
chemical_list: D007477:Ions; D010455:Peptides; D010748:Phosphopeptides; D011522:Protons; D016875:tau Proteins; D012694:Serine