 |
PDBsum entry 4m5t
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
The structured core domain of αb-Crystallin can prevent amyloid fibrillation and associated toxicity.
|
|
|
Authors
|
|
G.K.Hochberg,
H.Ecroyd,
C.Liu,
D.Cox,
D.Cascio,
M.R.Sawaya,
M.P.Collier,
J.Stroud,
J.A.Carver,
A.J.Baldwin,
C.V.Robinson,
D.S.Eisenberg,
J.L.Benesch,
A.Laganowsky.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2014,
111,
E1562.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Mammalian small heat-shock proteins (sHSPs) are molecular chaperones that form
polydisperse and dynamic complexes with target proteins, serving as a first line
of defense in preventing their aggregation into either amorphous deposits or
amyloid fibrils. Their apparently broad target specificity makes sHSPs
attractive for investigating ways to tackle disorders of protein aggregation.
The two most abundant sHSPs in human tissue are αB-crystallin (ABC) and HSP27;
here we present high-resolution structures of their core domains (cABC, cHSP27),
each in complex with a segment of their respective C-terminal regions. We find
that both truncated proteins dimerize, and although this interface is labile in
the case of cABC, in cHSP27 the dimer can be cross-linked by an intermonomer
disulfide linkage. Using cHSP27 as a template, we have designed an equivalently
locked cABC to enable us to investigate the functional role played by
oligomerization, disordered N and C termini, subunit exchange, and variable
dimer interfaces in ABC. We have assayed the ability of the different forms of
ABC to prevent protein aggregation in vitro. Remarkably, we find that cABC has
chaperone activity comparable to that of the full-length protein, even when
monomer dissociation is restricted through disulfide linkage. Furthermore, cABC
is a potent inhibitor of amyloid fibril formation and, by slowing the rate of
its aggregation, effectively reduces the toxicity of amyloid-β peptide to
cells. Overall we present a small chaperone unit together with its atomic
coordinates that potentially enables the rational design of more effective
chaperones and amyloid inhibitors.
|
|
|
|
|
|
|
