Folding Basics
Here’s the gist of it.
There’s a little machine made up of molecules in our cells called a “ribosome” which behaves like a little copying machine. It can build long chains of amino acids that we call “proteins” by making exact copies of small chunks of our master DNA blueprint. Proteins are the things that actually “do stuff” in our cells and as you can imagine they’re pretty important. Well, after our ribosome is finished copying off a protein chain, that protein instantly folds up into a more compact and job-specific shape and floats off to perform its task within our cells.
How does a protein know how to fold up? It’s very interesting. Different parts of the long protein chain have different properties. Some parts of the chain are attracted to water for instance, while some are repelled by water. Some parts have a small negative electrical charge while some are positively charged. These properties of a protein chain, when surrounded by other chemicals with their own properties (especially water), vigorously push and pull the protein into its folded shape. The final folded shape of a protein is critical since the bits that are on the outside determine what properties of the protein are exposed to its surroundings; these exposed properties and other things like the protein’s shape determine how the protein interacts with other molecules and their exposed properties and shapes to do work.
There are over 25,000 different proteins in our bodies doing all manner of things, none which we can live without and none of which we fully understand. And while a single protein fold might occur in just 1/10,000th of a second, it happens on a grand scale inside of our bodies’ cells billions of times a second.
Here’s a big sucker, it’s a type of protein called an enzyme (I used an image from the entry on Protein on Wikipedia):
Each one of the tiny little dots in the image is an atom and their connections are illustrated by the little rods.
Now believe it or not, that isn’t just a random wad. It’s a long chain which must fold up in to precisely that same complex shape every single time. If for some reason the protein does not fold into that shape one of two things can happen: our body can recognize that its made a mistake and destroy the molecule, or the molecule can continue to exist and start to cause problems by interacting improperly with surrounding molecules.
The improper interactions caused by mis-folding proteins can range anywhere from completely benign to instantly fatal. We call these problems “diseases”.
Huntington’s Disease and Folding (A little less basic)
Huntington’s Disease is the protein folding disorder that afflicts my father and uncle. Here’s how:
We all create a protein called Huntingtin which has to do with several important activities within our cells including the creation of another protein with the exciting name of BDNF. BDNF is used in brain cells as part of their life support and proper development.
In my father’s body, the portion of his DNA that describes the Huntingtin protein has a small flaw. There’s a section where where it’s supposed to repeat a series of molecules (cytosine-adenine-guanine (CAG)) 27 times or fewer as it does in me. My father’s DNA repeats this CAG pattern too many times. That thing, which is so simple to describe, prevents his Huntingtin proteins from folding correctly much of the time.
When my father’s Huntingtin proteins misfold, one of the problems that occurs is that now there are simply fewer correctly folded Huntingtin proteins around than are needed by his nuerons. Since my father has less correct Huntingtin protein in his brain cells, he creates less BDNF. Less BDNF means less support for his brain cells which causes them to die prematurely. In our brains the cells that govorn motor control are particuarly dependent upon BDNF which is why Huntington’s manifests itself as a motor control disease.
How many times CAG repeats in the Huntingtin protein determines how much of the time a Huntingtin protein misfolds and in turn how severe and how early Huntington’s Disease strikes. A normal number of repeats is below 27, while 36 to 39 repeats results in late onset and relatively mild HD. The largest recorded CAG repetition is approximately 250 shown in a boy who began showing symptoms at 2.5 years of age and died of Huntington’s at 16.
