46
Aggregation, Protein
protein component has been identifed.
In the 1970s, it was demonstrated that
lysosomal proteins under acidic condi-
tions could Form amyloid fbrils. It was
generally accepted at this time that prote-
olysis was the amyloidogenic determinant.
Twenty years later, it was shown that
purifed transthyretin is converted into
amyloid fbrils via an acid-induced conFor-
mational change
in vitro
,d
emon
s
t
r
a
t
ing
that conFormational changes alone were
responsible For producing an intermedi-
ate generating amyloid structure. These
aberrant protein selF-assemblies are at
the origin oF more than hundred human
amyloid diseases, some oF them being
lethal.
Twenty
unrelated
protein
precursors
are
known
to
Form
amyloid
fbrils,
among them transthyretin, lysozyme, im-
munoglobulin light chain,
β
2
microglob-
ulin, Alzheimer A
β
1–40 and A
β
1–42
peptides, the mammalian prion protein,
and the yeast prion-like proteins (Table 1).
Since they are subjects oF another chap-
ter, prion proteins will not be discussed
here. Although they have no homology
in sequence and structure, all Form amy-
loid fbrils with a similar overall struc-
ture, suggesting a common selF-assembly
Tab. 1
Amyloidogenic proteins and the corresponding diseases.
Clinical syndrome
Precursor protein
Fibril component
Alzeimer’s disease
APP
β
-peptide 1–40 to 1–43
Primary systemic amyloidosis
Immunoglobulin light chain
Intact light chain or fragments
Secondary systemic amyloidosis
Serum amyloid A
Amyloid A (76-residue
fragment)
Senile systemic amyloidosis
Transthyretin
Transthyretin or fragments
Familial amyloid polyneuropathy I
Transthyretin
Over 45 transthyretin variants
Hereditary cerebral amyloid
angiopathy
Cystatin C
Cystatin C minus 10 residues
Hemodialysis-related
β
2
-microglobulin
β
2
-microglobulin
amyloidosis
Apolipoprotein A1
Fragments of Apolipoprotein
A1
Familial amyloid polyneuropathy III
Gelsosin
71-amino acid fragment of
gelsosin
Finnish hereditory systemic
amyloidosis
Islet amyloid polypeptide
(IAPP)
Fragment of IAPP
Type II diabetes
Calcitonin
Fragments of calcitonin
Medullary carcinoma of the thyroid
Spongiform encephalopathies
Prion
Prion or fragments thereof
Atrial amyloidosis
Atrial natriuretic factor
(ANF)
ANF
Hereditary nonneuropathic systemic
amyloidosis
Lysozyme
Lysozyme or fragments
thereof
Injection-localized amyloidosis
Insulin
Insulin
Hereditary renal amyloidosis
Fibrinogen
Fibrinogen fragments
Parkinson disease
α
-synuclein
Source
: (According to Kelly, J.W. (1996) Alternative conformations of amyloidogenic proteins govern
their behavior,
Curr. Opin. Struct. Biol.
6
,11–17);
From J.C. Rochet & P.T. Lansbury (2000)
Curr.
Opin. Struct. Biol.
10
, 60–68.
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