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When proteins misbehave, part 2
1. WHEN PROTEINS MISBEHAVE (Part 2)
Proteostasis and its disorders
What is in common between the Japanese art of Origami and protein folding or
misfolding?
Origami is the traditional Japanese art of paper folding, which started in the 17th century.
The goal of this art is to transform a flat sheet of paper into a finished sculpture through
folding and sculpting techniques without cutting or gluing.
Protein folding is the art of life that Nature uses in our cells. It is the process by which a
protein structure assumes its functional shape or conformation by which a polypeptide
folds into its characteristic and functional three-dimensional structure.
http://www.youtube.com/watch?v=gFcp2Xpd29I
Each organism has thousands of different proteins, which define its nature. Like origami
paper, they can take the right path and fold into a sheep or take the wrong path and fold
into a wolf. The consequences of protein misfolding can be deadly, leading to devastating
neurodegenerative diseases.
The Proteins in our bodies come in all shapes and sizes: they can be round (like
haemoglobin), long (like collagen), strong (like spectrin c which protects erythrocytes
from the powerful shearing forces they are exposed to), or elastic (like titin, which
controls muscle stretching and contraction).
Our bodies contain more than 100,000 proteins that are produced from a set of only 20
amino acids. What makes this possible is posttranslational modification and folding of
proteins in a three dimensional structure. The question is how is the tertiary structure of
proteins encoded into the amino acid sequence? This is the part that we do not know yet.
Christian Anfinsen in the early 1960s investigated a ribonuclease enzyme, which he
isolated from the pancreatic tissue of cattle. This enzyme is made up of 124 amino acids
and it cleaves any ribonucleic acid (RNA) that could be harmful to the cell. Ribonuclease
can be denatured by adding certain chemicals or by heat. In various studies, Anfinsen
showed that this denaturation process could be completely reversed by removing these
denaturing chemicals or by lowering the temperature. In that situation, the ribonuclease
folded back to its natural functional state on its own. Anfinsen concluded that the amino-
acid sequence determines the three dimensional shape of a protein, a finding for which he
received the Nobel Prize in Chemistry in 1972.
.
Orderely protein folding is only possible under the supervision of specialized molecules,
called chaperones, which accompany proteins and make sure that those that are being
formed at the ribosomes do not clump together prematurely . Chaperones do not merely
2. oversee the folding of the protein, they also protect its tertiary structure in situations in
which the cell is under stress.
How the proteins fold exactly where they are supposed to fold is still a mistery. It seems
like they self assemble along invisible energy lines just like an unfolded origami paper
that seems to keep the memory of its previous shape. The word proteostasis was coined
to denote a sense of equilibrium that a protein tends to go to. This is a video of the
proteostasis of a virus:
http://www.youtube.com/watch?v=br-YxeXWx6s&feature=related
Although we are not quite clear how proteins fold, researchers have begun exploring
ways that can influence parts of this process. They learned that the disorders of
proteostasis are characterized by either:
-loss-of-function diseases such as cystic fibrosis, Gaucher’s disease and related
lysosomal storage diseases—the errant protein is targeted for early destruction.
-gain-of-function diseases, which include Huntington’s, Alzheimer’s, type 2 diabetes
and a group of illnesses called familial amyloidoses. In this case, instead of being
destroyed, misfolded proteins break down and form a toxic aggregates.
Treatments for proteostasis disorders
Loss-of function diseases
CFTR is the protein thought to cause many symptoms of cystic fibrosis. Its function is to
let chloride into and out of the cell. In its most common mutation, CFTR is missing one
amino acid, phenylalanine, which causes it to fold improperly. The endoplasmic
reticulum then destroys the mutant CFTR before it can reach the cell membrane.
A pharmacologically made exogenous chaperone protein can bind to CFTR while in the
endoplasmic reticulum and partially repair the misfolded protein by making it “look”
like normal CFTR. Even though such a repaired protein isn’t identical to its perfectly
folded counterparts, it was proved to function effectively both in vivo and in vitro.
Gain-of-function diseases
A type of chaperone that researchers call a kinetic stabilizer aims at binding to and
stabilizing a protein before the damage occurs, preserving it in its functional state.
Another approach, called a proteostasis regulator, aims at protecting the proteins from
early degradation and allowing them to reach their destination.
Treatments for Parkinson’s, Huntington’s, amyotrophic lateral sclerosis and amyloid
polyneuropathy may stem from discovering kinetic stabilizers or proteostasis regulator
proteins for these disorders.
3. Recently, FoldRx Therapeutics developed a drug, tafamadis meglumine (FX-1006A),
which is now in clinical trials for TTR amyloid polyneuropathy (an amyloid folding
disorder).
Possible Applications in Schizophrenia
The notion of disturbed proteostasis and protein aggregation as a mechanism of mental
diseases is emerging.
Korth C. from the Department of Neuropathology, Heinrich Heine University Düsseldorf,
Germany published a paper in April 2012, showing that DISC1 protein aggregates were
cell-invasive comparable to that of α-synuclein. Disease-associated DISC1 polymorphism
S704C led to a higher oligomerization tendency of DISC1. These findings justify
classification of DISC1-dependent brain disorders as protein conformational disorders
which were tentatively termed DISC1opathies.
http://www.ncbi.nlm.nih.gov/pubmed/22421208
ADONIS SFERA, MD