WHEN PROTEINS DO NOT FOLD PROPERLY....
IT MAY LEAD TO DISEASES...
like Alzheimer's disease. Cystic fibrosis. Mad Cow disease.
An inherited form of emphysema. Even many cancers.
Did you tangle up some proteins this morning? You probably did, if you fried
some eggs:
When we fry an egg, the proteins in the white unfold. But when the egg
cools, the proteins don't return to their original shapes. Instead, they
form a solid, insoluble (but tasty) mass. This is misfolding. Similarly,
biochemists have always had problems with the tendency of some proteins
to form the insoluble lumps in the bottom of their test tubes. We now
know that these, too, were proteins folded into the wrong shapes
To make proteins, molecular "machines" known as ribosomes string
together amino acids into long, linear chains. Like shoelaces, these chains
loop about each other in a variety of ways (i.e., they fold). But, as
with a shoelace, only one of these many ways allows the protein to function
properly. Yet lack of function is not always the worst scenario. For just
as a hopelessly knotted shoelace could be worse than one that won't stay
tied, too much of a misfolded protein could be worse than too little of
a normally folded one. This is because a misfolded protein can actually
poison the cells around it.
Proteins have to pass through partially folded states in which they
are delicately poised between folding all the way to the correct state
or becoming seriously stuck as a result of premature entanglement with
other molecules. Recognizing that it was the intermediates and not the
fully folded protein that were in trouble opened the way to understanding
some aspect of a range of diseases.
Alzheimer's Disease
Alzheimer's disease, afflicts 10 percent of those over 65 years old and
perhaps half of those over 85. Every year Alzheimer's not only kills 100,000
Americans, but also costs society $82.7 billion to care for its victims.
As far back as the start of this century, physicians have been noticing
that certain diseases are characterized by extensive protein deposits
in certain tissues. Most of these diseases are rare, but Alzheimer's is
not. It was Alois Alzheimer himself who noted the presence of "neurofibrillary
tangles and neuritic plaque" in certain regions of his patient's
brain.
In 1991, several different research groups found that individuals with
specific mutations in their amyloid precursor protein developed Alzheimer's
disease as early as age 40. The body processes amyloid precursor protein
into a soluble peptide (small protein) known as Ab; under certain circumstances,
Ab then aggregates into long filaments that cannot be cleared by the body's
usual scavenger mechanisms. These aggregates then form the b-amyloid,
which make up the neuritic plaque in Alzheimer patients. So the consistent
association of amyloid precursor protein mutations with early-onset Alzheimer's
has finally answered a long-debated question: the deposition of neuritic
plaque is part of the pathway leading to the disease, not a late consequence
of it.
Mad Cow Disease
Perhaps the most interesting example of a protein folding disorder is
Mad Cow disease and its human equivalent, Creutzfeldt-Jacob disease. These
diseases, along with the sheep version known as scrapie, have had the
scientific community in an uproar for years. They are infectious diseases
transmitted by prions, or protein particles. Prions seem to be pure protein;
they contain neither DNA nor RNA. Yet an infectious agent is necessarily
self-replicating. How, scientists asked themselves, could a pure protein
replicate itself?
The protein whose aggregation damages nerve cells in Mad Cow disease
is constantly being produced by the body. Normally, though, it folds properly,
remains soluble, and is disposed of without problem. But suppose that
somehow a small amount misfolds in a particular way so as to become a
scrapie prion. If this scrapie prion bumps into a normal-folding intermediate,
it shifts the folding process in the scrapie direction and the protein,
despite its perfectly normal amino acid sequence, ends up as more scrapie
prion. And the process continues: So long as the body keeps producing
the normal protein, a little bit of scrapie prion can keep on creating
more and then more. In effect, the prion is "replicating" itself
without needing any nucleic acid of its own.
Cystic Fibrosis, Cancer and Protein Misfolding
Recent research has clearly shown that the many, previously mysterious
symptoms of cystic fibrosis all derive from lack of a protein that regulates
the transport of the chloride ion across the cell membrane. More recently
scientists have shown that by far the most common mutation underlying
cystic fibrosis hinders the dissociation of the transport-regulator protein
from one of its chaperones. Thus, the final steps in normal folding cannot
occur, and normal amounts of active protein are not produced.
A hereditary form of emphysema shows an even greater analogy to the mutations
studies in P22 tailspike protein. Investigators have found that one of
the most common mutations producing this disorder greatly slows the normal
folding process, just as the P22 temperature-sensitive mutations do. As
with the tailspike mutations, the resulting buildup of a crucial folding
intermediate leads to aggregation, which deprives affected individuals
of enough circulating a1-antitrypsin to protect their lungs. Emphysema
is the result.
As intriguing as these examples may be, there is a far more common instance
of misfolding, which leaves too little normal protein to do its job. In
this case, the protein's job is to block cancer development.
Over the past couple of decades, scientists have learned that most cancers
result from mutation in the genes that regulate cell growth and cell division.
The most common of these genes, involved in roughly 40% of all human cancers,
is p53. The sole function of the p53 protein appears to prevent cells
with damaged DNA from dividing before the damage is repaired (or to induce
them to destroy themselves, if the damage cannot be fixed). In other words,
p53 exists to prevent cells from becoming cancerous.
p53 mutations associated with cancer fall into two classes. The first
keeps the protein from binding to DNA; the other makes the folded form
of the protein less stable. In the second group, there is simply never
enough properly folded protein around to block the division of DNA-damaged
cells. It will be interesting to see how many of the p53 mutants fall
into this second class and whether some way can be found to stabilize
them.
Treating Protein Misfolding
The purpose of studying any human disease is to find ways to treat it.
The story of protein folding has not yet led to treatments for the diseases
involved, but this could happen within the next decade.
The key is to find a small molecule, a drug that can either stabilize
the normally folded structure or disrupt the pathway that leads to a misfolded
protein. Of course before we can do that we have to have a better understanding
of how proteins fold. With distributed computing we may get the answers
a lot sooner.
Author: Tug Sezen
Reference: Federation of American Societies for Experimental Biology
(FASEB)
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