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PDBsum entry 2q1e
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Protein fibril
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PDB id
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2q1e
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References listed in PDB file
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Key reference
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Title
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Altered dimer interface decreases stability in an amyloidogenic protein.
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Authors
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E.M.Baden,
B.A.Owen,
F.C.Peterson,
B.F.Volkman,
M.Ramirez-Alvarado,
J.R.Thompson.
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Ref.
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J Biol Chem, 2008,
283,
15853-15860.
[DOI no: ]
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PubMed id
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Abstract
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Amyloidoses are devastating and currently incurable diseases in which the
process of amyloid formation causes fatal cellular and organ damage. The
molecular mechanisms underlying amyloidoses are not well known. In this study,
we address the structural basis of immunoglobulin light chain amyloidosis, which
results from deposition of light chains produced by clonal plasma cells. We
compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the
kappaI O18/O8 light chain germline. Crystallographic studies indicate that both
proteins form dimers. However, AL-09 has an altered dimer interface that is
rotated 90 degrees from the kappaI O18/O8 dimer interface. The three
non-conservative mutations in AL-09 are located within the dimer interface,
consistent with their role in the decreased stability of this amyloidogenic
protein. Moreover, AL-09 forms amyloid fibrils more quickly than kappaI O18/O8
in vitro. These results support the notion that the increased stability of the
monomer and delayed fibril formation, together with a properly formed dimer, may
be protective against amyloidogenesis. This could open a new direction into
rational drug design for amyloidogenic proteins.
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Figure 2.
FIGURE 2. In vitro fibril formation indicated shorter lag
time for AL-09. a, ThT fluorescence measured at 1, 24, and 120 h
indicated that AL-09 (  ) formed fibrils within
24 h, whereas  I O18/O8 (  ) did not
(error bars were ± S.D. for n = 5; ^*, p value 0.05).
Even after 120 h, I O18/O8 had not formed
fibrils (^**, p value 0.0079). Complete amyloid formation
kinetics followed by ThT fluorescence is included in
supplemental Fig. S2 online. b, electron micrograph of AL-09 at
24 h (scale bar, 500 nm), confirming fibril formation. c, I O18/O8
fibril formation at 215 h (scale bar 100 nm) confirms the
earliest time point at which ThT fluorescence enhancement
occurred (supplemental Fig. S2 online).
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Figure 3.
FIGURE 3. Crystal structures revealed different dimer
interfaces for I O18/O8 (a) and AL-09
(b). c, superposition of I O18/O8 (blue and
cyan) and AL-09 (brown and salmon) dimers illustrated that AL-09
had a 90° rotation from the canonical (germline-like)
interface. d, arrangement of key interface residues was
significantly disrupted upon superposition of I O18/O8
(blue) and AL-09 (brown) monomers. The presence of the second
monomers for I O18/O8 (cyan) and
AL-09 (salmon) showed that a canonical dimer interface in AL-09
was sterically impossible, given the conformation of F98 (yellow
highlight). e, stereo images of I O18/O8 2F[o]-F[c]
electron density (at 1  contouring). The images
show the electron density around Trp-35.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
15853-15860)
copyright 2008.
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