Protein folding
mechanisms and role in disease
P
roteins perform vital cellular
functions; however, in order to
work, these chain-like molecules
must fold into complex, threedimensional structures1 (Fig.1).
The process is quality controlled by complex
molecules within the cell2,3; however, it can
go awry, yielding misfolded proteins that
clump into toxic aggregates (Fig. 2). Many
age-related diseases, such as Alzheimer’s
disease, are thought to be caused by the
build-up of these aggregates4,5. A coordinated network of interdisciplinary
research is developing therapies that aim to
remove or prevent the build-up of these
misfolded proteins. If successful, their
potential to improve quality of life is
immense.
ProTein origami
Proteins are the workhorses of the cell: they
are essential molecules that fulfil vital and
diverse cellular functions, such as catalysing chemical reactions, providing structural support, and mediating cell signalling
and development. Human cells contain
thousands of proteins, each consisting of a
chain of 100–500 amino-acid building
blocks. In order to work, however, these
newly built proteins must first fold into a
complex yet highly specific three-dimensional shape.
With hundreds of thousands of different possible structures for each protein,
achieving the correct one is a tall order; yet,
most proteins manage to perform this task
quickly and efficiently. Larger proteins
tackle the problem by folding different
parts of the molecule separately. The
process is driven by hydrophobic and
hydrophilic properties of amino acids in
different sections of the protein. Waterrepelling amino acids interact with one
other to build a hydrophobic core, whereas
water-attracting amino acids settle on the
exterior of the protein. This causes the protein chain to collapse into a globular structure that forms a stable, three-dimensional, biologically active protein.
QualiTy conTrol
Given the complexity of the process, it is
no surprise that the cell has evolved its own
system of protein quality control. There are
specialized proteins dubbed molecular
chaperones, discovered in the late 1980s,
that help prevent aberrant folding by
shielding the sticky hydrophobic surfaces
of unfolded or misfolded proteins. The
members of one notable class of molecular
chaperone, the chaperonins, take the form
of tiny cylindrical cages with lids (Fig. 3).
Unfolded proteins enter the cage and are
protected as they fold, then released when
the lid opens. Furthermore, each cell has a
proteasome: a cylindrical complex that
breaks up unneeded or misfolded proteins
into small fragments, which can then be
recycled to make new proteins.
Despite this sophisticated system of
quality control, things can go wrong and
misfolded proteins can accumulate. Aberrant folding can have dire consequences, as
misfolded proteins might be unable to fulfil their biological roles. This can happen in
two ways: the protein is either incorrectly
constructed in the first place or loses its
shape later in its lifetime. Examples of the
former include mutations in the gene that
encodes the tumour-suppressing protein
p53, which can result in an incorrectly folded version of the p53 protein that cannot
repair damaged — and potentially cancercausing — snippets of DNA. Similarly, an
inherited mutation in a key gene can trigger the formation of the misfolded protein
that underlies cystic fibrosis.
As well as crippling protein function,
R
esearch at the max Planck institute of Biochemistry has provided
insight into the mechanisms by which molecular chaperones
can prevent the build-up of toxic protein aggregates in cells.
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Research Perspectives of the Max Planck Society | 2010+
aberrant folding can have other serious
effects. Misfolded proteins can clump
together to form insoluble aggregates
that accumulate inside or around cells.
It is thought that this build-up of
cellular debris impairs cell functioning and
is toxic to the cell. Cell death caused by
the build-up of toxic aggregates is
hypothesized to be a key feature of many
age-related degenerative neurological
disorders, including Huntington’s and
Alzheimer’s diseases4,5.
The ravages of Time
Research suggests that our protein qualitycontrol system functions less well with
age, explaining why we might become
more prone to the build-up of misfolded,
potentially disease-causing proteins6. The
brains of people with Alzheimer’s disease,
for example, are riddled with hallmark
misfolded protein aggregates called amyloid
plaques. The plaques build up around
nerve cells and, although it is not clear
whether these aggregates are a cause or a
consequence of the disease, it is thought
that they contribute to cell death and
memory loss.
The realization that protein misfolding
might underlie a number of age-related
diseases offers the opportunity to develop
a generic therapy to address this group of
economically costly and increasingly prevalent ailments. It has already been shown
through a tissue-culture study that antibiotic treatment can boost the expression of
several molecular chaperones and prevent
the aggregation of mutant huntingtin protein, which causes Huntington’s disease7.
Although we understand protein folding at a basic level, its intricacies have yet
to be revealed and key questions remain.
How does our protein quality-control system work and why does it begin to fail
This remarkable ability of chaperones could form the basis for the
development of novel strategies in the fight against neurodegenerative
diseases (Behernds, C. et al. Mol. Cell 23, 887–897, 2006).
BIOLOGY AND MEDICINE
Proteins are chain-like molecules. in order to function properly, they must
fold into complex three-dimensional shapes.
The failure of proteins to fold properly has been linked to various diseases,
including cancer, huntington’s disease and alzheimer’s disease.
understanding protein folding will aid the development of therapies that
remove or prevent the formation of misfolded protein clumps.
Fig. 1 | X-ray crystallographic characterization of a
three-dimensionally folded maltose-binding protein.
with age? Why are misfolded proteins toxic to cells? What are they like structurally
and how do they interact with the rest of
the cell? How can we remove toxic protein
aggregates or prevent their formation?
It is likely that the answers will hold
major medical significance, as reflected by
substantial research initiatives in the US,
UK and Japan. Moreover, protein-folding
studies, which were formerly merely of academic interest, are now the focus of
intense applied therapeutic research.
50 Å
0.000005 mm
geTTing iT TogeTher
The challenge in understanding protein
folding is in the pooling of relevant
knowledge from different disciplines.
Computer simulations and biophysical
methods will help reveal the molecular
features of protein aggregates; the toxicity
of these aggregates will be assessed in
tissue culture and animal models8. A
technique called quantitative proteomics
will help explain how misfolded proteins
become toxic. Furthermore, research on
the cellular quality-control system should
shed light on how the cell controls its
normal protein balance and any agerelated changes. The goal is to help explain
ageing and its associated diseases, and to
develop relevant therapies.
Molecules that interfere directly with
aggregate formation are already in development, as are strategies aiming to
activate the defence mechanisms of the
cell — chaperones and protein-degrading
enzymes — to do the job9,10. Screening of
large libraries of compounds will help
identify new aggregate-busting and chaperone-activating molecules, and then
drug-discovery researchers will assess any
such molecules preclinically.
A detailed understanding of normal
and aberrant protein folding is likely to
require an integrated, interdisciplinary
approach. This knowledge has the potential to improve our healthy lifespan and
offer treatments for age-related disorders
that are currently without cure.
➟ For references see pages 38 and 39
Fig. 2 | Schematic representation of protein folding.
Jc[daYZY
EgdeZgan[daYZY
egdiZ^c
Idm^XegdiZ^c
Xajbe
Fig. 3 | Action of the chaperonin protein.
2010+ | Research Perspectives of the Max Planck Society
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