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PDBsum entry 3d0t
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* Residue conservation analysis
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Enzyme class:
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Chains A, B, C, D:
E.C.?
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DOI no:
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Nat Struct Biol
15:1309-1317
(2008)
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PubMed id:
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Structural basis of nucleotide exchange and client binding by the Hsp70 cochaperone Bag2.
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Z.Xu,
R.C.Page,
M.M.Gomes,
E.Kohli,
J.C.Nix,
A.B.Herr,
C.Patterson,
S.Misra.
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ABSTRACT
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Cochaperones are essential for Hsp70- and Hsc70-mediated folding of proteins and
include nucleotide-exchange factors (NEFs) that assist protein folding by
accelerating ADP-ATP exchange on Hsp70. The cochaperone Bag2 binds misfolded
Hsp70 clients and also acts as an NEF, but the molecular basis for its function
is unclear. We show that, rather than being a member of the Bag domain family,
Bag2 contains a new type of Hsp70 NEF domain, which we call the 'brand new bag'
(BNB) domain. Free and Hsc70-bound crystal structures of Bag2-BNB show its
dimeric structure, in which a flanking linker helix and loop bind to Hsc70 to
promote nucleotide exchange. NMR analysis demonstrates that the client binding
sites and Hsc70-interaction sites of the Bag2-BNB overlap, and that Hsc70 can
displace clients from Bag2-BNB, indicating a distinct mechanism for the
regulation of Hsp70-mediated protein folding by Bag2.
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Selected figure(s)
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Figure 1.
(a) Comparison between domain organizations of Bag2 and
Bag1S, the shortest isoform of Bag1. The C-terminal domain of
each protein binds to Hsp70 and has NEF activity. (b) Cartoon
representations of the Bag2-BNB dimer, related by an
approximately 90° rotation. Dotted lines indicate the
disordered linker loops of each monomer. (c) Structure of the
Bag1-Bag domain^8 (PDB 1HX1). (d) Packing between protomers of
the Bag2-BNB dimer. Side chains of nonpolar residues are shown
as spheres. (e) Sedimentation velocity analysis of Bag2-BNB
(left) and Bag2 (right) at 48,000 r.p.m. (186,000g) and 20
°C. The sedimentation coefficient distribution c(s) of
Bag2-BNB shows a single species corresponding to a dimer, in
agreement with the crystal structure, whereas Bag2 shows
multiple species. Mass estimates suggest that the large peak
corresponds to a tetramer (Supplementary Table 1).
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Figure 2.
(a) The asymmetric unit of the crystal, containing two
Hsc70-NBD molecules and a Bag2-BNB dimer. (b) Closer view of the
interface between the Bag2-BNB dimer and one of the Hsc70-NBD
molecules. The BNB dimer contacts Hsc70-NBD subdomains Ib and
IIb, largely through the Bag2 linker loop and  L
helix. (c) Close-up view of contacts between the Bag2-BNB linker
loop and residues on subdomain Ib of Hsc70-NBD. Dotted lines
represent likely hydrogen bonds or salt bridges. (d) Close-up
view of contacts between the Bag2-BNB dimer and subdomain IIb of
Hsc70-NBD. (e) Close-up view of additional contacts between
Bag2-BNB and subdomain IIb of Hsc70-NBD. This view is related to
that in d by a rotation of approximately 180° about the
vertical axis.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
Nat Struct Biol
(2008,
15,
1309-1317)
copyright 2008.
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Figures were
selected
by the author.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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L.V.Kalia,
S.K.Kalia,
H.Chau,
A.M.Lozano,
B.T.Hyman,
and
P.J.McLean
(2011).
Ubiquitinylation of α-Synuclein by Carboxyl Terminus Hsp70-Interacting Protein (CHIP) Is Regulated by Bcl-2-Associated Athanogene 5 (BAG5).
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PLoS One,
6,
e14695.
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A.Arakawa,
N.Handa,
N.Ohsawa,
M.Shida,
T.Kigawa,
F.Hayashi,
M.Shirouzu,
and
S.Yokoyama
(2010).
The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
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Structure,
18,
309-319.
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PDB codes:
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C.Andréasson,
H.Rampelt,
J.Fiaux,
S.Druffel-Augustin,
and
B.Bukau
(2010).
The endoplasmic reticulum Grp170 acts as a nucleotide exchange factor of Hsp70 via a mechanism similar to that of the cytosolic Hsp110.
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J Biol Chem,
285,
12445-12453.
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J.C.Young
(2010).
Mechanisms of the Hsp70 chaperone system.
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Biochem Cell Biol,
88,
291-300.
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M.Wisniewska,
T.Karlberg,
L.Lehtiö,
I.Johansson,
T.Kotenyova,
M.Moche,
and
H.Schüler
(2010).
Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B', and HSPA5/BiP/GRP78.
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PLoS One,
5,
e8625.
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PDB codes:
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H.J.Woo,
J.Jiang,
E.M.Lafer,
and
R.Sousa
(2009).
ATP-induced conformational changes in Hsp70: molecular dynamics and experimental validation of an in silico predicted conformation.
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Biochemistry,
48,
11470-11477.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
