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

Hua Li, Seizo Koshiba, Fumiaki Hayashi, Naoya Tochio, Tadashi Tomizawa, Takuma Kasai, Takashi Yabuki, Yoko Motoda, Takushi Harada, Satoru Watanabe, Makoto Inoue, Yoshihide Hayashizaki, Akiko Tanaka, Takanori Kigawa, Shigeyuki Yokoyama

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20 Citations (Scopus)

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 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 a2.5-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.

Original languageEnglish
Pages (from-to)27165-27178
Number of pages14
JournalJournal of Biological Chemistry
Volume283
Issue number40
DOIs
Publication statusPublished - 2008 Oct 3
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Li, H., Koshiba, S., Hayashi, F., Tochio, N., Tomizawa, T., Kasai, T., Yabuki, T., Motoda, Y., Harada, T., Watanabe, S., Inoue, M., Hayashizaki, Y., Tanaka, A., Kigawa, T., & Yokoyama, S. (2008). 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. Journal of Biological Chemistry, 283(40), 27165-27178. https://doi.org/10.1074/jbc.M803892200