 |
PDBsum entry 2e1e
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Crystal structure of the hrdc domain of human werner syndrome protein, Wrn.
|
|
|
Authors
|
|
K.Kitano,
N.Yoshihara,
T.Hakoshima.
|
|
|
Ref.
|
|
J Biol Chem, 2007,
282,
2717-2728.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Werner syndrome is a human premature aging disorder characterized by chromosomal
instability. The disease is caused by the functional loss of WRN, a member of
the RecQ-helicase family that plays an important role in DNA metabolic pathways.
WRN contains four structurally folded domains comprising an exonuclease, a
helicase, a winged-helix, and a helicase-and-ribonuclease D/C-terminal (HRDC)
domain. In contrast to the accumulated knowledge pertaining to the biochemical
functions of the three N-terminal domains, the function of C-terminal HRDC
remains unknown. In this study, the crystal structure of the human WRN HRDC
domain has been determined. The domain forms a bundle of alpha-helices similar
to those of Saccharomyces cerevisiae Sgs1 and Escherichia coli RecQ.
Surprisingly, the extra ten residues at each of the N and C termini of the
domain were found to participate in the domain architecture by forming an
extended portion of the first helix alpha1, and a novel looping motif that
traverses straight along the domain surface, respectively. The motifs combine to
increase the domain surface of WRN HRDC, which is larger than that of Sgs1 and
E. coli.In WRN HRDC, neither of the proposed DNA-binding surfaces in Sgs1 or E.
coli is conserved, and the domain was shown to lack DNA-binding ability in
vitro. Moreover, the domain was shown to be thermostable and resistant to
protease digestion, implying independent domain evolution in WRN. Coupled with
the unique long linker region in WRN, the WRN HRDC may be adapted to play a
distinct function in WRN that involves protein-protein interactions.
|
|
|
|
|
|
|
|
Figure 2.
FIGURE 2. Crystal structure of the human WRN HRDC domain.
A, front view (left) and top view (right) of WRN HRDC in a
ribbon model. Secondary structure elements are labeled, and
dimensions of the molecule are indicated. Molecular surface of
the domain is shown in transparent gray (conventional HRDC core)
and red (N- and C-terminal extensions unique to WRN). B,
superimposition of WRN HRDC (green) with Sgs1 (19) (pink) and E.
coli (20) (yellow) HRDCs. The orientation is the same as in A.
The N and C termini of each molecule are labeled.
Superimposition was performed using LSQMAN (56).
|
|
Figure 3.
FIGURE 3. C-terminal extended loop packed to the HRDC core.
A,a stick model represents carbon atoms of the nine C-terminal
residues (1227–1235, labeled with one-letter codes) shown in
cyan, whereas the other part of the domain including N-terminal
extended helix  1 is in green. The
composite-omit density map (25) for the C-terminal residues is
shown at the contour level of 1  . The orientation is
similar to that in Fig. 2A (top view). B, schematic
representation depicting the interactions between the C-terminal
extended loop (cyan) and HRDC core, including helix 1(green). Hydrogen
bonds are shown as dashed lines with distances (Å) shown.
Two hydrophobic pockets on the HRDC core (pocket-1 formed by
side chains from Thr^1152, Phe^1222, Cys^1223, and Asn^1226, and
pocket-2 formed by Met^1190, Pro^1192, Asn^1197, Ile^1201, and
Arg^1200) that are important for the binding of C-terminal
residues are indicated.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2007,
282,
2717-2728)
copyright 2007.
|
|
|
|
|
|
|
