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PDBsum entry 2nyt
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References listed in PDB file
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Key reference
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Title
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The apobec-2 crystal structure and functional implications for the deaminase aid.
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Authors
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C.Prochnow,
R.Bransteitter,
M.G.Klein,
M.F.Goodman,
X.S.Chen.
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Ref.
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Nature, 2007,
445,
447-451.
[DOI no: ]
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PubMed id
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Abstract
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APOBEC-2 (APO2) belongs to the family of apolipoprotein B messenger RNA-editing
enzyme catalytic (APOBEC) polypeptides, which deaminates mRNA and
single-stranded DNA. Different APOBEC members use the same deamination activity
to achieve diverse human biological functions. Deamination by an APOBEC protein
called activation-induced cytidine deaminase (AID) is critical for generating
high-affinity antibodies, and deamination by APOBEC-3 proteins can inhibit
retrotransposons and the replication of retroviruses such as human
immunodeficiency virus and hepatitis B virus. Here we report the crystal
structure of APO2. APO2 forms a rod-shaped tetramer that differs markedly from
the square-shaped tetramer of the free nucleotide cytidine deaminase, with which
APOBEC proteins share considerable sequence homology. In APO2, two long
alpha-helices of a monomer structure prevent the formation of a square-shaped
tetramer and facilitate formation of the rod-shaped tetramer via head-to-head
interactions of two APO2 dimers. Extensive sequence homology among APOBEC family
members allows us to test APO2 structure-based predictions using AID. We show
that AID deamination activity is impaired by mutations predicted to interfere
with oligomerization and substrate access. The structure suggests how mutations
in patients with hyper-IgM-2 syndrome inactivate AID, resulting in defective
antibody maturation.
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Figure 2.
Figure 2: The APO2 active site. a, The APO2 active sites are
accessible to DNA/RNA. Red spheres represent Zn. b, The fntCDA
active site is accessible only to free nucleotides. c, The outer
APO2 active sites show Zn coordination (yellow dashed lines) by
three residues (H98, C128, C131) and a water molecule (blue
sphere). d, The middle APO2 active centre sites show Zn
coordination by a fourth residue, E60. e, In the  1'-hairpin
structure, the hydrophobic ring of Y61 interacts with the
guanidine group of R65, stabilizing the conformation. f, In the
h1/ 1
loop, the E60 coordinates with Zn. Y61 now rotates away from R65
and interacts with R57, facilitating the disruption of the 1'-hairpin
and stabilizing the loop conformation. g, Superimposed monomers
show that the h1/ 1
loop (purple) is pulled down  8.5
Å towards the active site owing to the E60–Zn bond
formation.
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Figure 4.
Figure 4: AID HIGM-2 mutations.
Figure 4 : AID
HIGM-2 mutations. Unfortunately we are unable to provide
accessible alternative text for this. If you require
assistance to access this image, or to obtain a text
description, please contact npg@nature.com-
a, Alignment of mutated residues of AID from HIGM-2 patients
with the corresponding residues in APO2, showing high sequence
conservation. b, Mapping the residues in AID HIGM-2 mutations
(R112, L113, N168) to the tetramer interface as modelled from
the APO2 structure. c, Mapping the AID HIGM-2 mutations, S83 and
S85, near the active site. d, Mapping the AID mutations, K16,
Y114/F115 and C116 (in green), to the exposed surface of an
outer monomer. The HIGM-2 AID residues (R112, L113, N168, in
yellow), which are at the tetramer interface (b), are also
located on this exposed surface. e, Mapping of AID HIGM-2
mutations, W80, L106, M139 and F151, to the interior core
structure.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2007,
445,
447-451)
copyright 2007.
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