Three-Dimensional Structure of Proteins
of abnormal prion protein. The conversion of the normal
prion protein, whose function is unknown, to an aberrant
form involves a conformational change rather than a co-
valent modification. The abnormal prion protein functions
as a seed that induces the normal cellular prion protein to-
wards the abnormal amyloidogenic rich, /1-structure pro-
teins which can be propagated and transmitted to other
cells. The aggregated form of prion protein forming amy-
loid is resistant to proteolysis.
sensitive prion protein to a protease-resistanct form oc-
curs in vitro by mixing the two proteins. However, these
protease-resistant prion proteins are not infectious. Thus,
in the “protein-only” hypothesis of prion infection, the
acquisition of an abherrant conformation is not sufficient
for the propagation of infectivity. However, in the yeast
(Saccharomyces cerevisiae)
system, the abnormal prion
form of the yeast protein, introduced by liposome fusion,
is able to seed a self-propagating conformational change
of the normal proteins, which accumulate as aggregates.
The aggregates are transmissible to daughter yeast cells
along with the propagation of abnormal phenotype.
Recently a serious public health problem has arisen by
showing that a prion disease in cattle can cross species bar-
riers and infect humans. This occurred when cattle were
fed meal made from sheep infected with scrapie. The cat-
tle developed BSE (commonly called “mad cow disease”).
Subsequently, when people consumed prion-contaminated
beef, a small number, primarily in Great Britain, devel-
oped a variant of CJD (vCJD) approximately five years
afterward. The variant form of CJD is a unique form of
prion disease occurring in a much younger population than
would be expected from inherited or sporadic CJD. Both
BSE and vCJD share many similar pathologic character-
istics suggesting an etiologic link between human vCJD
and cattle BSE.
The tumor suppressor protein
provides yet another
example of protein misfolding that can lead to pathological
effects, in this case cancers
is for protein and 53 is for
its approximate molecular weight of 53,000). The gene for
is located on the short arm of chromosome 17 (17/?)
and codes for a 393-amino-acid phosphoprotein. In many
cancers the
gene is mutated and the lack of normal
protein has been linked to the development of as many
as 40% of human cancers.
functions as a tumor suppressor and is a
transcription factor that normally participates in the reg-
ulation of several genes required to control
cell growth,
DNA repair,
(programmed cell death). Nor-
is a tetramer and it binds to DNA in a sequence-
specific manner. One of the p53-regulated genes produces
a protein known as
, which interferes with the cell cycle
by binding to cyclin kinases. Other genes regulated by
are MDM2 and BAX. The former gene codes for a protein
that inhibits the action of
by functioning as a part of
a regulatory feedback mechanism. The protein made by
the BAX gene is thought to play a role in p53-induced
Most mutations of
genes are somatic missense
mutations involving amino acid substitutions in the DNA
binding domain. The mutant forms of
are misfolded
proteins with abnormal conformations and the inability
to bind to DNA, or they are less stable. Individuals with
the rare disorder
Li-Fraumeni syndrome,
(an autosomal
dominant trait) have one mutated
gene and one normal
gene. These individuals have increased susceptibility
to many cancers, such as leukemia, breast carcinomas,
soft-tissue sarcomas, brain tumors, and osteosarcomas.
Clinical trials are underway to investigate whether the
introduction of normal
gene into tumor cells by means
of gene therapy (Chapter 23) has beneficial effects in the
treatment of cancer. Early results with
gene ther-
apy indicate that it may shrink the tumor by triggering
Supplemental Readings and References
Protein Folding and Its Defects
R. Aurora, T. R Creamer, R. Srinivasan and G. D. Rose: Local interactions in
protein folding: Lessons from thear-helix.
Journal of Biological Chemistry
1 1 1 ,
J. R. Beasley and M. H. Hecht: Protein design: The choice of de novo
Journal of Biological Chemistry
1 1 1 ,
2031 (1997).
M. Blaber, X.-J. Zhang, and B. W. Mathews: Structural basis of amino acid
a-helix propensity.
260, 1637 (1993).
R. W. Carrell and D. A. Lomas: Conformational disease.
350, 134
W. D. Kohn, C. T. Mant, and R. S. Hodges: a-helical protein assembly
Journal of Biological Chemistry
1 1 1 ,
2583 (1997).
R. W. Ruddon and E. Bedows: Assisted protein folding.
Journal of Biological
1 1 1 ,
3125 (1997).
P. J. Thomas, B.-H. Qu, and P. L. Pedersen: Defective protein folding as a
basis of human disease.
Trends in Biochemical Sciences
20, 456 (1995).
Alzheimer’s Disease,
and Prions
J. Avila: Tau aggregation into fibrillar polymers: taupathies.
FEBS Letters
89 (2000).
A. Bossers, R. de Vries, M. A. Smits: Susceptibility of sheep for scrapie as
assessed by in vitro conversion of nine naturally occurring variants of PrP.
Journal of Virology
1407 (2000).
F. E. Cohen: Prion, peptides and protein misfolding.
Molecular Medicine
6,292 (2000).
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