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

132 Chapter 3: Proteins
Figure 3–33 The special protein aggregates that cause prion diseases.
(A) Schematic illustration of the type of conformational change in the PrP
protein (prion protein) that produces material for an amyloid fibril. (B) The selfinfectious
nature of the protein aggregation that is central to prion diseases.
PrP is highly unusual because the misfolded version of the protein, called
PrP*, induces the normal PrP protein it contacts to change its conformation,
as shown.
Amyloid Structures Can Perform Useful Functions in Cells
Amyloid fibrils were initially studied because they cause disease. But the same type
of structure is now known to be exploited by cells for useful purposes. Eukaryotic
cells, for example, store many different peptide and protein hormones that they
will secrete in specialized “secretory granules,” which package a high concentration
of their cargo in dense cores with a regular structure (see Figure 13–65). We
now know that these structured cores consist of amyloid fibrils, which in this case
have a structure that causes them to dissolve to release soluble cargo after being
secreted by exocytosis to the cell exterior (Figure 3–34A). Many bacteria use the
amyloid structure in a very different way, secreting proteins that form long amyloid
fibrils projecting from the cell exterior that help to bind bacterial neighbors
into biofilms (Figure 3–34B). Because these biofilms help bacteria to survive in
adverse environments (including in humans treated with antibiotics), new drugs
that specifically disrupt the fibrous networks formed by bacterial amyloids have
promise for treating human infections.
Many Proteins Contain Low-complexity Domains that Can Form
“Reversible Amyloids”
Until recently, those amyloids with useful functions were thought to be either
confined to the interior of specialized vesicles or expressed on the exterior of cells,
as in Figure 3–34. However, new experiments reveal that a large set of low complexity
domains can form amyloid fibers that have functional roles in both the
cell nucleus and the cell cytoplasm. These domains are normally unstructured
and consist of stretches of amino acid sequence that can span hundreds of amino
acids, while containing only a small subset of the 20 different amino acids. In contrast
to the disease-associated amyloid in Figure 3–33, these newly discovered
structures are held together by weaker noncovalent bonds and readily dissociate
in response to signals—hence their name reversible amyloids.
Many proteins with such domains also contain a different set of domains that
bind to specific other protein or RNA molecules. Thus, their controlled aggregation
(A) prion protein can adopt an abnormal,
misfolded form
normal Prp
protein
(B)
very rare
conformational
change
misfolded protein can induce formation
of protein aggregates
Prp
heterodimer
homodimer
protein aggregate in
form of amyloid fibril
abnormal prion form
of PrP protein (Prp*)
Prp*
misfolded protein converts
normal PrP into abnormal
conformation
the conversion of more
PrP to misfolded form
creates a stable amyloid
fibril
secreted amyloid fibril
releases soluble peptide
hormone
MBoC6 e4.08/3.31
PLASMA MEMBRANE
amyloid fibril on
bacterial surface
(A)
secretory
granule
Golgi
cisterna
processed
peptide
hormone
fusion
budding
amyloid
fibril
template
subunit
(B)
subunit
of fibril
peptidoglycan
layer
bacterial
membrane
Figure 3–34 Two normal functions for
amyloid fibrils. (A) In eukaryotic cells,
protein cargo can be packed very densely
in secretory vesicles and stored until
signals cause a release of this cargo by
exocytosis. For example, proteins and
peptide hormones of the endocrine system,
such as glucagon and calcitonin, are
efficiently stored as short amyloid fibrils,
which dissociate when they reach the cell
exterior. (B) Bacteria produce amyloid fibrils
on their surface by secreting the precursor
proteins; these fibrils then create biofilms
that link together, and help to protect, large
numbers of individual bacteria.