B. Prion diseases
The prion protein (PrP) has been strongly implicated as the causative
agent of transmissible spongiform encephalopathies (TSEs), including
Creutzfeldt-Jakob disease in humans, scrapie in sheep, and bovine
spongiform encephalopathy in cattle (popularly called “mad cow” dis-
ease). After an extensive series of purification procedures, scientists
were surprised to find that the infectivity of the agent causing scrapie
in sheep was associated with a single protein species that was not
complexed with detectable nucleic acid. This infectious protein is
designated PrP
Sc
(Sc = scrapie). It is highly resistant to proteolytic
degradation and tends to form insoluble aggregates of fibrils, similar
to the amyloid found in some other diseases of the brain. A nonin-
fectious form of PrP
C
(C = cellular), encoded by the same gene as
the infectious agent, is present in normal mammalian brains on the
surface of neurons and glial cells. Thus, PrP
C
is a host protein. No
primary structure differences or alternate posttranslational modifica-
tions have been found between the normal and the infectious forms of
the protein. The key to becoming infectious apparently lies in changes
in the three-dimensional conformation of PrP
C
. It has been observed
that a number of
α
‑helices present in noninfectious PrP
C
are replaced
by
β
-sheets in the infectious form (Figure 2.14). It is presumably this
conformational difference that confers relative resistance to proteolytic
degradation of infectious prions and permits them to be distinguished
from the normal PrP
C
in infected tissue. The infective agent is, thus,
an altered version of a normal protein, which acts as a “template” for
converting the normal protein to the pathogenic conformation. The
TSEs are invariably fatal, and no treatment is currently available that
can alter this outcome.
VII. CHAPTER SUMMARY
Central to understanding protein structure is the concept of the
native
conformation
(Figure 2.15), which is the functional, fully folded protein
structure (for example, an active enzyme or structural protein). The unique
three-dimensional structure of the native conformation is determined by its
primary structure
, that is, its amino acid sequence. Interactions between
the amino acid side chains guide the folding of the polypeptide chain to
form
secondary
,
tertiary
, and (sometimes)
quaternary
structures, which
cooperate in stabilizing the native conformation of the protein. In addition,
a specialized group of proteins named
chaperones
is required for the
proper folding of many species of proteins.
Protein denaturation
results
in the unfolding and disorganization of the protein’s structure, which are not
accompanied by hydrolysis of peptide bonds. Denaturation may be revers-
ible or, more commonly, irreversible. Disease can occur when an appar-
ently normal protein assumes a conformation that is cytotoxic, as in the
case of Alzheimer disease and the
transmissible spongiform encepha-
lopathies
(
TSEs
), including
Creutzfeldt-Jakob disease
. In
Alzheimer
disease,
normal proteins, after abnormal chemical processing, take on a
unique conformational state that leads to the formation of neurotoxic
amy-
loid
β
peptide
(
A
β
)
assemblies consisting of
β
-pleated sheets. In TSEs, the
infective agent is an altered version of a normal
prion protein
that acts as
a “template” for converting normal protein to the pathogenic conformation.
22
2. Structure of Proteins
Figure 2.14
One proposed mechanism for
multiplication of infectious prion
agents. PrP = prion protein;
PrP
c
= prion protein cellular;
PrP
Sc
= prion protein scrapie.
Infectious PrP
Sc
(contains
β
-sheets)
Infectious PrP
Sc
(contains
β
-sheets)
This results in an exponential
increase of the infectious form.
3
1
Interaction of the infectious
PrP molecule with a normal
PrP causes the normal form
to fold into the infectious form.
Noninfectious PrP
C
(contains
α
-helix)
Noninfectious PrP
C
(contains
α
-helix)
Noninfectious PrP
C
(contains
α
-helix)
2
These two molecules dissociate
and convert two additional non-
infectious PrP molecules to the
infectious form.
02_Structure_proteins.indd 22
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