Crystal structure of the human Fe65-PTB1 domain.
The neuronal adaptor protein Fe65 is involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP. It contains three protein-protein interaction domains, one WW domain, and a unique tandem array of phosphotyrosine-binding (PTB) domains. The N-terminal PTB domain (Fe65-PTB1) was shown to interact with a variety of proteins, including the low density lipoprotein receptor-related protein (LRP-1), the ApoEr2 receptor, and the histone acetyltransferase Tip60. We have determined the crystal structures of human Fe65-PTB1 in its apo- and in a phosphate-bound form at 2.2 and 2.7A resolution, respectively. The overall fold shows a PTB-typical pleckstrin homology domain superfold. Although Fe65-PTB1 has been classified on an evolutionary basis as a Dab-like PTB domain, it contains attributes of other PTB domain subfamilies. The phosphotyrosine-binding pocket resembles IRS-like PTB domains, and the bound phosphate occupies the binding site of the phosphotyrosine (Tyr(P)) within the canonical NPXpY recognition motif. In addition Fe65-PTB1 contains a loop insertion between helix alpha2 and strand beta2(alpha2/beta2 loop) similar to members of the Shc-like PTB domain subfamily. The structural comparison with the Dab1-PTB domain reveals a putative phospholipid-binding site opposite the peptide binding pocket. We suggest Fe65-PTB1 to interact with its target proteins involved in translocation and signaling of APP in a phosphorylation-dependent manner.
Heidelberg University Biochemistry Center, INF328, D-69120 Heidelberg, Germany.
Jens
J
Radzimanowski
Stéphanie
S
Ravaud
Sabine
S
Schlesinger
Joachim
J
Koch
Konrad
K
Beyreuther
Irmgard
I
Sinning
Klemens
K
Wild
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C091042:APBB1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019000:Phosphotyrosine