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PDBsum entry 2fk3
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Metal binding protein
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PDB id
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2fk3
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References listed in PDB file
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Key reference
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Title
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Structural studies of the alzheimer'S amyloid precursor protein copper-Binding domain reveal how it binds copper ions.
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Authors
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G.K.Kong,
J.J.Adams,
H.H.Harris,
J.F.Boas,
C.C.Curtain,
D.Galatis,
C.L.Masters,
K.J.Barnham,
W.J.Mckinstry,
R.Cappai,
M.W.Parker.
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Ref.
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J Mol Biol, 2007,
367,
148-161.
[DOI no: ]
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PubMed id
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Abstract
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Alzheimer's disease (AD) is the major cause of dementia. Amyloid beta peptide
(Abeta), generated by proteolytic cleavage of the amyloid precursor protein
(APP), is central to AD pathogenesis. APP can function as a metalloprotein and
modulate copper (Cu) transport, presumably via its extracellular Cu-binding
domain (CuBD). Cu binding to the CuBD reduces Abeta levels, suggesting that a Cu
mimetic may have therapeutic potential. We describe here the atomic structures
of apo CuBD from three crystal forms and found they have identical Cu-binding
sites despite the different crystal lattices. The structure of Cu(2+)-bound CuBD
reveals that the metal ligands are His147, His151, Tyr168 and two water
molecules, which are arranged in a square pyramidal geometry. The site resembles
a Type 2 non-blue Cu center and is supported by electron paramagnetic resonance
and extended X-ray absorption fine structure studies. A previous study suggested
that Met170 might be a ligand but we suggest that this residue plays a critical
role as an electron donor in CuBDs ability to reduce Cu ions. The structure of
Cu(+)-bound CuBD is almost identical to the Cu(2+)-bound structure except for
the loss of one of the water ligands. The geometry of the site is unfavorable
for Cu(+), thus providing a mechanism by which CuBD could readily transfer Cu
ions to other proteins.
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Figure 2.
Figure 2. The structure of CuBD[133-189] in Type A crystal
form. This ribbon diagram of apo CuBD[133-189] is shown in
stereo view and prepared using BOBSCRIPT.^63 Key residues
surrounding the Cu-binding pocket are shown in ball-and-stick.
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Figure 4.
Figure 4. The coordination geometry of Cu^2+ and Cu^+ in CuBD
and comparison against the apo Type A structure. (a) The Cu^2+
binding geometry in CuBD[133-189]. The ligands are labeled (eq
and ax denote the equatorial and axial water molecules). (b) A
comparison of the Cu-binding site in the presence (atomic
coloring) and absence (grey, apo form) of the Cu^2+. (c) The
Cu^+ binding geometry in CuBD[133-189]. (d) A comparison of the
Cu-binding site in the presence (atomic coloring) and absence
(grey, apo form) of the Cu^+. All panels are in stereo view. The
orange sphere represents the Cu^2+ in (a) and (b) or Cu^+ in (c)
and (d). The red spheres are water molecules. The
2F[obs]–F[calc] electron density is shown in (a) and (c) in
blue mesh and contoured at 1σ level. All Figures were prepared
using the program PyMol (DeLano Scientific LLC, San Carlos, CA).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
367,
148-161)
copyright 2007.
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