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When proteins misbehave, part 2
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When proteins misbehave, part 2

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  • 1. WHEN PROTEINS MISBEHAVE (Part 2)Proteostasis and its disordersWhat is in common between the Japanese art of Origami and protein folding ormisfolding?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 throughfolding 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 aprotein structure assumes its functional shape or conformation by which a polypeptidefolds into its characteristic and functional three-dimensional structure.http://www.youtube.com/watch?v=gFcp2Xpd29IEach organism has thousands of different proteins, which define its nature. Like origamipaper, they can take the right path and fold into a sheep or take the wrong path and foldinto a wolf. The consequences of protein misfolding can be deadly, leading to devastatingneurodegenerative diseases.The Proteins in our bodies come in all shapes and sizes: they can be round (likehaemoglobin), long (like collagen), strong (like spectrin c which protects erythrocytesfrom the powerful shearing forces they are exposed to), or elastic (like titin, whichcontrols muscle stretching and contraction).Our bodies contain more than 100,000 proteins that are produced from a set of only 20amino acids. What makes this possible is posttranslational modification and folding ofproteins in a three dimensional structure. The question is how is the tertiary structure ofproteins 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 heisolated from the pancreatic tissue of cattle. This enzyme is made up of 124 amino acidsand it cleaves any ribonucleic acid (RNA) that could be harmful to the cell. Ribonucleasecan be denatured by adding certain chemicals or by heat. In various studies, Anfinsenshowed that this denaturation process could be completely reversed by removing thesedenaturing chemicals or by lowering the temperature. In that situation, the ribonucleasefolded 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 hereceived 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 beingformed 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 inwhich the cell is under stress.How the proteins fold exactly where they are supposed to fold is still a mistery. It seemslike they self assemble along invisible energy lines just like an unfolded origami paperthat seems to keep the memory of its previous shape. The word proteostasis was coinedto denote a sense of equilibrium that a protein tends to go to. This is a video of theproteostasis of a virus:http://www.youtube.com/watch?v=br-YxeXWx6s&feature=relatedAlthough we are not quite clear how proteins fold, researchers have begun exploringways that can influence parts of this process. They learned that the disorders ofproteostasis are characterized by either:-loss-of-function diseases such as cystic fibrosis, Gaucher’s disease and relatedlysosomal storage diseases—the errant protein is targeted for early destruction.-gain-of-function diseases, which include Huntington’s, Alzheimer’s, type 2 diabetesand a group of illnesses called familial amyloidoses. In this case, instead of beingdestroyed, misfolded proteins break down and form a toxic aggregates.Treatments for proteostasis disordersLoss-of function diseasesCFTR is the protein thought to cause many symptoms of cystic fibrosis. Its function is tolet chloride into and out of the cell. In its most common mutation, CFTR is missing oneamino acid, phenylalanine, which causes it to fold improperly. The endoplasmicreticulum then destroys the mutant CFTR before it can reach the cell membrane.A pharmacologically made exogenous chaperone protein can bind to CFTR while in theendoplasmic 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 perfectlyfolded counterparts, it was proved to function effectively both in vivo and in vitro.Gain-of-function diseasesA type of chaperone that researchers call a kinetic stabilizer aims at binding to andstabilizing a protein before the damage occurs, preserving it in its functional state.Another approach, called a proteostasis regulator, aims at protecting the proteins fromearly degradation and allowing them to reach their destination.Treatments for Parkinson’s, Huntington’s, amyotrophic lateral sclerosis and amyloidpolyneuropathy may stem from discovering kinetic stabilizers or proteostasis regulatorproteins 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 foldingdisorder).Possible Applications in SchizophreniaThe notion of disturbed proteostasis and protein aggregation as a mechanism of mentaldiseases 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 werecell-invasive comparable to that of α-synuclein. Disease-associated DISC1 polymorphismS704C led to a higher oligomerization tendency of DISC1. These findings justifyclassification of DISC1-dependent brain disorders as protein conformational disorderswhich were tentatively termed DISC1opathies.http://www.ncbi.nlm.nih.gov/pubmed/22421208ADONIS SFERA, MD