BioPHYSICAL chemistry

of very real importance as such aggregates are

linked to many diseases that cannot be treated,

including Alzheimer’s disease, Creutzfeldt–

Jakob disease, and bovine spongiform ence-

phalopathy (so-called mad-cow disease). The

involvement of misfolded proteins giving rise

to these diseases was initially met with skepti-

cism, but the efforts of Stanley Pruisner in the

1980s (Prusiner 1987) have led to a general

acceptance as recognized by a Nobel Prize in

Medicine in 1997.

Whereas these proteins, which are termed

prions, for proteinaceous infectious particles,

usually have a globular shape, they can also

adopt a structure that leads to formation of

amyloid-like fibrils (Zahn et al. 2000; Dobson

2003; Masison 2004; May et al. 2004; Dyson

& Wright 2005; Krishnan & Lindquist 2005;

Nelson et al. 2005). Proteins in amyloid fibrils

are folded to form continuous arrays of βsheets.

A large portion of a prion is folded in a com-

pact globular arrangement with αhelices and

βsheets, with a sizable portion of the protein

missing due to disorder, including most of

the first 100 amino acid residues (Zahn et al.

2000; Figure 8.5).

The determination of the arrangement of

prions in amyloid fibrils has been hampered

by the limited order of fibrils isolated from

diseased tissues. A seven-residue fragment

has been shown by X-ray diffraction to form

βsheets in the crystal structure (Figure 8.6;

Nelson et al. 2005). One of the mysteries of

prions is why one misfolded protein can drive

a conformational chain reaction resulting in

other folded proteins becoming misfolded.

Although the mechanism of self-assembly

remains unknown, the tendency of peptide

fragments to form β sheets suggests the

involvement of specific parts of the protein.

The process should involve the N-terminal

domain of the prion forming an intermediate

state similar to those proposed above. How-

ever, this intermediate state is driven away

from a globular form to a structure that results

in formation of amyloid fibroids.

170 PARTI THERMODYNAMICS AND KINETICS

Side chain

on inner face

Side chain

on outer face

Fibril axis

Figure 8.6The crystal structure of a seven-
residue peptide from the yeast prion Sup35,
showing the β-sheet arrangement of the peptide.
From Nelson et al. (2005).

Figure 8.5The NMR structure of a prion showing
a well-defined globular domain. The open,
extended region was not resolved in the
NMR data.