Yeast Prions: Their Assembly into Protein Fibrils and the Role of Assembly Modulators - The Functional Fold: Amyloid Structures in Nature - page 101

n *

stable nucleus P at its ends, is

formed as the energy gained from intermolecular interactions does
not outweigh the entropic cost of binding. A number of inherited
mutations that destabilize yeast prions predispose them to convert
to their unstable P

, that can grow by incorporation of P

* 71,72

thus, increasing the concentration of
the latter form and favouring their oligomerization. The requirement
for stable nuclei to form before conversion is stable accounts for the
low frequency of occurrence of the prion phenotypes. However, the
high efficiency of incorporation of P

form,

*

into oligomers and polymers

*

made of P and breakage of the polymers into smaller units, each

being a potential seed, accounts for the efficiency of transmission
from mother to daughter cells.

6.6 Structural Models at an Atomic Resolution

for Fibrillar Prion Proteins

High-resolution three-dimensional structures for prion proteins, in
particular yeast prions, are not yet available. A number of models
have been built mainly from low-resolution structural information
obtained from fragments of the proteins and by analogy to high-
resolution structural data obtained for short peptides (7-15 amino
acid residues long) that do not necessarily have prion properties.

73-75

These working models should be manipulated with extreme caution
as they may not reflect the authentic structures of the fibrillar
form of full-length prion proteins. Nevertheless, biochemical and
cellular data provide interesting information on the packing of prion
molecules within the fibrils they form.
As mentioned previously, prion proteins are peculiar in that the
same polypeptide chain can misfold into structurally distinct protein
aggregates at the origin of distinguishable phenotypes named
“prion strains” or “variants”.

20,76-78

A set of data based on side-chain
modification of amino acid residues located within the N-terminal
domain of Sup35p NM fragment mutational analysis, cross-linking,
NMR, and peptide arrays studies suggest that sub-regions within
the region spanning residues 1-121 form the core of Sup35pNM
fibrils. The length of these sub-regions is still subject to debate.
Indeed, while data suggest that a significant portion of residues in
the region spanning residues 1-121, residues 31-86, and 21-121

79

establish intermolecular contacts and form the core of distinct