Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

THE SHAPE AND STRUCTURE OF PROTEINS
131
Figure 3–31 Detailed structure of the core of an amyloid fibril. Illustrated here
is the cross-beta spine of the amyloid fibril that is formed by a peptide of seven
amino acids from the protein Sup35, an extensively studied yeast prion. Consisting
of the sequence glycine-asparagine-asparagine-glutamine-glutamine-asparaginetyrosine
(GNNQQNY), its structure was determined by X-ray crystallography.
Although the cross-beta spines of other amyloids are similar, being composed of
two long β sheets held together by a “steric zipper,” different detailed structures
are observed depending on the short peptide sequence involved. (A) One half
of the spine is illustrated. Here, a standard parallel β-sheet structure (see
p. 116) is held together by a set of hydrogen bonds between two side chains plus
hydrogen bonds between two backbone atoms, as illustrated (oxygen atoms red
and nitrogen atoms blue). Note that in this example, the adjacent peptides are
exactly in register. Although only five layers are shown (each layer depicted as an
arrow), the actual structure would extend for many tens of thousands of layers
in the plane of the paper. (B) The complete cross-beta spine. A second, identical
β-sheet is paired with the first one to form a two-sheet motif that runs the entire
length of the fibril. (C) View of the complete spine in (B) from the top. The closely
interdigitated side chains form a tight, water-free junction known as a steric zipper.
(Courtesy of David Eisenberg and Michael Sawaya, UCLA; based on R. Nelson et
al., Nature 435:773–778, 2005. With permission from Macmillan Publishers Ltd.)
(A)
side chain
H-bond
backbone
H-bond
tissue containing the protein aggregate. A set of closely related diseases—scrapie
in sheep, Creutzfeldt–Jakob disease (CJD) in humans, Kuru in humans, and
bovine spongiform encephalopathy (BSE) in cattle—are caused by a misfolded,
aggregated form of a particular protein called PrP (for prion protein). PrP is normally
located on the outer surface of the plasma membrane, most prominently in
neurons, and it has the unfortunate property of forming amyloid fibrils that are
“infectious” because they convert normally folded molecules of PrP to the same
pathological form (Figure 3–33). This property creates a positive feedback loop
that propagates the abnormal form of PrP, called PrP*, and allows the pathological
conformation to spread rapidly from cell to cell in the brain, eventually causing
death. It can be dangerous to eat the tissues of animals that contain PrP*, as witnessed
by the spread of BSE (commonly referred to as “mad cow disease”) from
cattle to humans. Fortunately, in the absence of PrP*, PrP is extraordinarily difficult
to convert to its abnormal form.
A closely related “protein-only inheritance” has been observed in yeast cells.
The ability to study infectious proteins in yeast has clarified another remarkable
feature of prions. These protein molecules can form several distinctively different
types of amyloid fibrils from the same polypeptide chain. Moreover, each type of
aggregate can be infectious, forcing normal protein molecules to adopt the same
type of abnormal structure. Thus, several different “strains” of infectious particles
can arise from the same polypeptide chain.
(B)
(C)
cross-beta spine
cross-beta spine
MBoC6 n3.317/3.30.5
(A)
relatively undefined peripheral domains
(B)
2 nm
(C)
100 nm
Figure 3–32 The structure of an amyloid
fibril. (A) Schematic diagram of the
structure of a amyloid fibril that is formed
by the aggregation of a protein. Only
the cross-beta spine of an amyloid fibril
resembles the structure shown in Figure
3–31. (B) A cut-away view of a structure
proposed for the amyloid fibril that can
be formed in a test tube by the enzyme
ribonuclease A, illustrating how the core
of the fibril—formed by a short segment—
relates to the rest of the structure.
(C) Electron micrograph of amyloid fibrils.
(A, from L. Esposito, C. Pedone and
L. Vitagliano, Proc. Natl Acad. Sci. USA
103:11533–11538, 2006; B, from S.
Sambashivan et al., Nature 437:266–269,
2005; C, courtesy of David Eisenberg.)