August 03, 2007

Protein Folding And Disease: Nature's Own Origami

origami, the art of paper foldingHuman body is like a very complicated computer. It's code (genetic) is written in 4 letters: Adenine, Cytosine, Guanine and Thymine, compared to 2 letters (0,1) in computers. But in our cases, this code is again translated into another language using 20 letters, the 20 amino acids, genes produce by the way of transcription and translation. This language of the proteins that forms, as a result of combinations (and permutations) of these amino acids, is not a word for word (verbatim) dictation by the human genome. Genes only tell the order in which one protein would arrange itself like the beads in a string, where the beads are individual amino acids.

Proteins then fold themselves (much like origami: the ancient Japanese art of paper folding), adding another dimension to this language. This folding is dictated by numerous factors like charge, hydrophilicity, hydrophobicity, van der Waals forces, hydrogen bonding etc. Once they fold upon themselves, they are accompanied by chaperone proteins, so that this configuration is preserved (like write protecting in computers). Any misfolding, due to aging or some other defect, is severely dealt with by a peptide consisting of 74 amino acids, called ubiquitin. It tags the defectively folded proteins to be destroyed, for removal, in a multi unit intracellular factory called proteasome, in much the same way a Windows computer would tag a file to be deleted to the recycle bin. Many diseases occur from misfolded proteins, Alzheimer's disease, Prion diseases like bovine spongiform encephalopathy or mad cow disease etc. In Alzheimer's for example, a protein named beta amyloid accumulates in the brain. We normally produce beta amyloid in our brains, but this amyloid is in soluble form. Proteins consist of both water dissolving (hydrophilic) and water non dissolving (hydrophobic) amino acids. In normal beta amyloid, the hydrophilic domains lie outward while the hydrophobic domains are kept in the interior. Thus, it remains soluble in the interstitial body fluids. But when this protein is misfolded, the hydrophobic domains are exposed, making it immiscible in water, allowing it to aggregate in clumps, called neurofibrillary tangles. This tangle presumably strangles the neurones and causes AD. Thus it is necessary that we understand the property of the tertiary structures (foldings) of proteins, in order to deal with such diseases.

Recently, scientists have developed a unique way to explore this. They are using atomic force microscopes (AFM) to have an understanding of this. They tied one terminal (end) of a protein to a substrate (serving as an anchor) and stretched the other end, which were tied to a very tiny cantilever, a part of the AFM itself. Then they released this (cantilever end) and measured the intermediate energy it released, as it went back to the equilibrium point (previous state), reminding us of the way we measured the energy stored in a spring (isn't it?). This 3D shaping as a function of energy, a measurable and objective quantity, would definitely help us decipher the enigmatic coils of proteins, thus help us tackle these deadly and disabling ailments effectively.
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