title: Structure of the C-terminal phosphotyrosine interaction domain of Fe65L1 complexed with the cytoplasmic tail of amyloid precursor protein reveals a novel peptide binding mode.
abstract: Fe65L1, a member of the Fe65 family, is an adaptor protein that interacts with the cytoplasmic domain of Alzheimer amyloid precursor protein (APP) through its C-terminal phosphotyrosine interaction/phosphotyrosine binding (PID/PTB) domain. In the present study, the solution structures of the C-terminal PID domain of mouse Fe65L1, alone and in complex with a 32-mer peptide (DAAVTPEERHLSKMQQNGYENPTYKFFEQMQN) derived from the cytoplasmic domain of APP, were determined using NMR spectroscopy. The C-terminal PID domain of Fe65L1 alone exhibits a canonical PID/PTB fold, whereas the complex structure reveals a novel mode of peptide binding. In the complex structure, the NPTY motif forms a type-I beta-turn, and the residues immediately N-terminal to the NPTY motif form an antiparallel beta-sheet with the beta5 strand of the PID domain, the binding mode typically observed in the PID/PTB.peptide complex. On the other hand, the N-terminal region of the peptide forms a 2.5-turn alpha-helix and interacts extensively with the C-terminal alpha-helix and the peripheral regions of the PID domain, representing a novel mode of peptide binding that has not been reported previously for the PID/PTB.peptide complex. The indispensability of the N-terminal region of the peptide for the high affinity of the PID-peptide interaction is consistent with NMR titration and isothermal calorimetry data. The extensive binding features of the PID domain of Fe65L1 with the cytoplasmic domain of APP provide a framework for further understanding of the function, trafficking, and processing of APP modulated by adapter proteins.
authors.affiliation: Systems and Structural Biology Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Seizo
authors.initials: S
authors.lastname: Koshiba
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Hayashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Tochio
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tomizawa
authors.forename: Takuma
authors.initials: T
authors.lastname: Kasai
authors.forename: Takashi
authors.initials: T
authors.lastname: Yabuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Motoda
authors.forename: Takushi
authors.initials: T
authors.lastname: Harada
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Takanori
authors.initials: T
authors.lastname: Kigawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides