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PDBsum entry 1xwh
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Transcription
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PDB id
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1xwh
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References listed in PDB file
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Key reference
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Title
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Nmr structure of the first phd finger of autoimmune regulator protein (aire1). Insights into autoimmune polyendocrinopathy-Candidiasis-Ectodermal dystrophy (apeced) disease.
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Authors
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M.J.Bottomley,
G.Stier,
D.Pennacchini,
G.Legube,
B.Simon,
A.Akhtar,
M.Sattler,
G.Musco.
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Ref.
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J Biol Chem, 2005,
280,
11505-11512.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal
recessively inherited disease: autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a
multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers.
The first PHD finger of AIRE1 is a mutational hot spot, to which several
pathological point mutations have been mapped. Using heteronuclear NMR
spectroscopy, we determined the solution structure of the first PHD finger of
AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the
domain. We performed a conformational analysis of pathological AIRE1-PHD1
mutants that allowed us to rationalize the structural impact of APECED-causing
mutations and to identify an interaction site with putative protein ligands of
the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD
finger fold, with a highly conserved tryptophan buried inside the structure. The
PHD finger is stabilized by two zinc ions coordinated in an interleaved
(cross-brace) scheme. This zinc coordination resembles RING finger domains,
which can function as E3 ligases in the ubiquitination pathway. Based on this
fold similarity, it has been suggested that PHD fingers might also function as
E3 ligases, although this hypothesis is controversial. At variance to a previous
report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3
ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1
and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure
is clearly distinct from the RING finger fold. Our results point to a function
of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in
some APECED mutations.
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Figure 1.
FIG. 1. The three-dimensional structure of the AIRE1-PHD1
domain. A, multiple sequence alignment of PHD and RING finger
domains. Zinc-binding residues and the conserved Trp are marked
with asterisks (*). Sites of APECED-causing mutations are marked
with a red plus (+). Secondary structure elements of AIRE1-PHD1
are shown above the alignment. B, stereo-view representation of
the backbone atoms (N, C  , C') for residues
295-344 of an NMR ensemble of 20 structures. Secondary structure
elements are in blue, the loops and random coil in gray, the
variable loop L3 in yellow, the zinc ions in pink, and the
commonly conserved Trp residue side chain in cyan. C, ribbon
representation of AIRE1-PHD1 (same orientation as B, showing the
side chains (cyan) and atoms (sulfur in yellow, nitrogen in
green) of the zinc-coordinating residues, plus the conserved
Trp335 (cyan).
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Figure 5.
FIG. 5. Location and structural effects of APECED causing
mutations. 1H-1D spectra (amide region) of pathological mutants
of AIRE1-PHD1 and of wild-type AIRE1-PHD1 and AIRE1-PHD2. A,
mutant C311Y; B, AIRE1-PHD1 wild type upon addition of 20 mM
EDTA; C, mutant P326Q; D, mutant P326L; asterisks indicate the
presence of additional conformers, possibly coming from a
cis-trans isomerization of P325; E, mutant V301M; F, wild-type
AIRE1 PHD1, and G, wild-type AIRE1-PHD2; H, ribbon
representation of the AIRE1-PHD1 structure (blue) and mapping of
pathological point mutations by showing their side chains in
red; the zinc-binding residues are in cyan, the cis-proline
Pro325 in yellow, and the zinc ions in pink. I, space-filled
representation of AIRE1-PHD1, with pathological mutation sites
in red, Pro325 in yellow and zinc ions in pink. Val301 and
Pro326 are partially exposed to the surface.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
11505-11512)
copyright 2005.
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