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

• Published in: The Journal of biological chemistry Vol. 283; no. 40; pp. 27165 - 27178
• Main Authors: Li, Hua, Koshiba, Seizo, Hayashi, Fumiaki, Tochio, Naoya, Tomizawa, Tadashi, Kasai, Takuma, Yabuki, Takashi, Motoda, Yoko, Harada, Takushi, Watanabe, Satoru, Inoue, Makoto, Hayashizaki, Yoshihide, Tanaka, Akiko, Kigawa, Takanori, Yokoyama, Shigeyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.10.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Motifs - physiology; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animals; Mice; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peptides - chemistry; Peptides - genetics; Peptides - metabolism; Protein Binding - physiology; Protein Folding; Protein Structure, Quaternary - physiology; Protein Structure, Tertiary - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M803892200

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 β-turn, and the residues immediately N-terminal to the NPTY motif form an antiparallel β-sheet with the β5 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 α-helix and interacts extensively with the C-terminal α-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.