Aggregation, Protein
49
Recent observations from Dobson and
his group have shown that several pro-
teins unrelated to amyloid diseases are
able to aggregate
in vitro
into amyloid
Fbrils when exposed to mild denaturing
conditions. These Fbrils are indistinguish-
able from those found in pathological
conditions. It was demonstrated for dif-
ferent proteins such as normal lysozyme,
an SH
3
domain of a phosphatidyl in-
ositol protein kinase (±ig. 11), an acyl
phosphatase, and an
α
-helical protein,
myoglobin suggesting a common mech-
anism
for
the
formation
of
amyloid.
These Fndings clearly indicate that amy-
loid formation is a general property of
polypeptide chains rather than one re-
stricted to deFnite sequences as occurs
with
chameleon
sequences
capable
of
adopting either a
β
-o
ran
α
-helicoidal
structure depending on their environment.
±urthermore, these aggregates exhibited
an inherent toxicity when incubated with
mouse Fbroblasts. Several groups sug-
gest that oligomeric intermediates rather
than Fbrils themselves are responsible for
pathogenicity.
SigniFcant progress has been made in
understanding the mechanisms involved
in the formation of amyloid Fbrils. This
is an important step in guiding research
into
the
discovery
of
molecules
with
therapeutic efFciency.
See
also
Circular
Dichroism
in
Protein Analysis.
Bibliography
Books and Reviews
Dobson, C.M.,
ˇ
Sali, A., Karplus, M. (1998)
Protein folding. A perspective from theory
and experiment,
Angew. Chem. Int. Ed.
37
,
868–893.
Ellis, R.J. (1991) Molecular chaperones,
Ann. Rev.
Biochem.
60
, 321–347.
Ellis, R.J., Hartl, ±.U. (1999) Principles of protein
folding in the cellular environment,
Curr.
Opin. Struct. Biol.
9
, 102–110.
Georgiou, G., de Bernadez-Clark, E. (Eds.) (1991)
Protein Refolding
, ACS Symposium Series 470,
American Chemical Society, Washington, DC.
Gh´elis, C.,
Yon, J.M.
(1982)
Protein
folding
,
Academic Press, New York.
Jaenicke, R. (1987) ±olding and association of
proteins,
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Kim, P.S., Baldwin, R.L. (1990) Intermediates in
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Schlunegger, M.P., Bennett, M.J., Eisenberg, D.
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swapping: a model for protein assembly and
disassembly,
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, 61–122.
Wetlaufer, D.B., Ristow, S. (1973) Acquisition of
the three-dimensional structure of proteins,
Ann. Rev. Biochem.
42
, 135–158.
References of Primary Literature
Altamiro,
M.M.,
Garcia,
C.,
Possani,
L.D.,
±ersht,
A.R.
(1999)
Oxidative
refolding
chromatography: folding of the scorpion toxin
Cn5,
Nat. Biotechnol.
17
, 187–191.
AnFnsen, C.B. (1973) Principles that govern the
folding of polypeptide chains,
Science
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223–230.
AnFnsen, C.B., Haber, E., Sela, M., White, ±.H.
(1961) The kinetics of formation of native
ribonuclease during oxidation of the reduced
polypeptide chain,
Proc. Natl. Acad. Sci. USA
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, 1309–1314.
Baneyx,
±.
(1999)
Recombinant
protein
expression in Escherichia coli,
Curr. Opin.
Biotechnol.
10
, 411–421.
Bennett, M.J.,
Choe, S.,
Eisenberg, D.
(1994)
Domain
swapping:
Entangling
alliance
between proteins,
Proc. Natl. Acad. Sci. USA
91
, 3127–3131.
Bergdoll, M.,
Remy, M.H.,
Capron, C.,
Mas-
son, J.M., Dumas, P. (1997) Proline-dependent
oligomerization with arm exchange,
Structure
5
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de Bernadez-Clark, E. (2001) Protein refolding
for industrial processes,
Curr. Opin. Biotechnol.
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, 202–207.
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