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PDBsum entry 2oa8
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Hydrolase/DNA
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PDB id
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2oa8
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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 crystal structure of trex1 explains the 3' Nucleotide specificity and reveals a polyproline ii helix for protein partnering.
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Authors
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U.De silva,
S.Choudhury,
S.L.Bailey,
S.Harvey,
F.W.Perrino,
T.Hollis.
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Ref.
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J Biol Chem, 2007,
282,
10537-10543.
[DOI no: ]
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PubMed id
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Abstract
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The TREX1 enzyme processes DNA ends as the major 3' --> 5' exonuclease activity
in human cells. Mutations in the TREX1 gene are an underlying cause of the
neurological brain disease Aicardi-Goutières syndrome implicating TREX1
dysfunction in an aberrant immune response. TREX1 action during apoptosis likely
prevents autoimmune reaction to DNA that would otherwise persist. To understand
the impact of TREX1 mutations identified in patients with Aicardi-Goutières
syndrome on structure and activity we determined the x-ray crystal structure of
the dimeric mouse TREX1 protein in substrate and product complexes containing
single-stranded DNA and deoxyadenosine monophosphate, respectively. The
structures show the specific interactions between the bound nucleotides and the
residues lining the binding pocket of the 3' terminal nucleotide within the
enzyme active site that account for specificity, and provide the molecular basis
for understanding mutations that lead to disease. Three mutant forms of TREX1
protein identified in patients with Aicardi-Goutières syndrome were prepared
and the measured activities show that these specific mutations reduce enzyme
activity by 4-35,000-fold. The structure also reveals an 8-amino acid
polyproline II helix within the TREX1 enzyme that suggests a mechanism for
interactions of this exonuclease with other protein complexes.
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Figure 1.
FIGURE 1. The TREX1 dimer in complex with ssDNA. The TREX1
exonuclease dimerizes about a 2-fold axis perpendicular to the
 -strands (monomers shown
in blue and green). This interaction creates an extended
anti-parallel -sheet through the core
of the dimer and places the two active sites on opposite outer
edges. The complex contains ssDNA (shown as sticks) and Ca^2+
(shown as red spheres) bound in both of the active sites.
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Figure 4.
FIGURE 4. TREX1 structure reveals PPII helix. a, the
non-repetitive proline-rich region within TREX1 forms a PPII.
The PPII helix, made up of residues 54–62, has a tight,
3-sided, left-handed secondary structure. PPII helices often
function as interaction motifs with other proteins containing
SH3, WW, or EVH1 domains. b, location of PPII helices (shown in
red) within the TREX1 dimer. The positioning on opposite outer
edges of the same face of the dimer might play a key role in
TREX1 protein interactions by allowing for simultaneous binding
of multiple interaction domains to the dimer.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
10537-10543)
copyright 2007.
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