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PDBsum entry 3d8f
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Protein binding
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PDB id
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3d8f
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the human fe65-Ptb1 domain.
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Authors
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J.Radzimanowski,
S.Ravaud,
S.Schlesinger,
J.Koch,
K.Beyreuther,
I.Sinning,
K.Wild.
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Ref.
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J Biol Chem, 2008,
283,
23113-23120.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 3.
Phosphate binding to Fe65-PTB1 suggests
phosphotyrosine-dependent peptide interactions. A, close-up view
of the Fe65-PTB1 Tyr(P) binding pocket. The hydrogen-bonding
network of the phosphate group is indicated by dashed lines. B,
superposition of phosphate-bound Fe65-PTB1 with the IRS-1 PTB
domain (PDB code 1irs). The bound NPApY motif of the bound
peptide to IRS-1 is shown together with the two respective IRS-1
arginine residues of the binding pocket (gray). C,
phosphate-bound Fe65-PTB1 superposed to the Dab1/APP
nonphosphorylated peptide, including the NPTY motif (PDB code
1oqn).
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Figure 4.
The putative phospholipid-binding site. A, Fe65-PTB1 (color
ramps as in Figs. 2 and 3) superposed with the
Dab1-PTB-APP-IP[3] complex (PDB code 1oqn) shown in gray and
black. Residues involved in IP[3] binding and the equivalent
three arginines of Fe65-PTB1 are given. Although helix α2 in
Dab1 is elongated by two turns, Fe65-PTB1 contains a long and
flexible α2/β2 loop. B, electrostatic surface potential of the
Dab1-PTB domain showing the highly positively charged
phospholipid binding crown responsible for IP[3] binding (stick
model). Color scheme is as in Fig. 2. C, Fe65-PTB1 oriented in
the same way with superposed IP[3] taken from the Dab1-PTB
structure.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
23113-23120)
copyright 2008.
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Secondary reference #1
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Title
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Mercury-Induced crystallization and sad phasing of the human fe65-Ptb1 domain.
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Authors
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J.Radzimanowski,
S.Ravaud,
K.Beyreuther,
I.Sinning,
K.Wild.
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Ref.
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Acta Crystallogr Sect F Struct Biol Cryst Commun, 2008,
64,
382-385.
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PubMed id
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