Proteins — friends, but sometimes fiends

Our body makes a variety of molecules. We make proteins, nucleic acids, carbohydrates, lipids, and other molecules that we need for our body processes. Molecules that we need, but which we do not make ourselves, we take from our surroundings.

Take proteins. There are proteins that we need to support our body structures, proteins that we use as enzymes, proteins that we use to fight germs, and proteins that we use for various other purposes. Proteins are rightfully called the workhorses of our body because they do most of the work needed to keep our body functioning — and functioning properly.

Through eons of evolution, every protein that we now make (probably) has a structure that is best suited for its intended purpose. (There may still be room for improvement — who knows.)

Like all other molecules, the structure of a protein molecule depends on its constituent parts. With proteins, those are amino acids. There are 20 naturally occurring amino acids, each different from the others and each with different properties and reactivities that we incorporate into our proteins. The three-dimensional structure of a protein and its overall properties therefore depend on how those amino acids are arranged and how they interact with each other.

The proteins in our body find themselves in different environments. Some are completely exposed to the outside world, some are in our gut, some are in our blood, some are inside cells, some are on the outside of cells, some are by themselves, some are associated with other molecules, some are in aqueous environments, some are in oily surroundings, and so on. Their structures have to be well suited to their environment if they are to function properly.

And proteins normally do function properly — except in some cases.

To function properly, a protein molecule has to have a proper (three-dimensional) structure. In protein structure parlance, it is said to be “folded” properly. If it isn’t, it is said to be “misfolded.” There is a very small energy difference between a properly folded and a misfolded protein — only about 10 kcal/mol — so that a protein may just have a “normal” propensity to misfold. A change of just one amino acid in the protein could result in misfolding.

Misfolded protein molecules often become insoluble and aggregate to form “amyloids.” Amyloids are known to be the cause of various diseases.

Examples of diseases caused by amyloids are Alzheimer’s disease (most common cause of dementia), Parkinson’s disease (loss of movement control), Amyotrophic lateral sclerosis (often referred to as Lou Gehrig’s disease, caused by loss of voluntary muscle control), among others.

Because of the small energy difference between a properly folded and a misfolded protein, protein molecules that tend to misfold may even recruit normal molecules to form aggregates — and cause disease. Such protein molecules are called “prions” (infectious proteins). Examples of prion diseases are Creutzfeld-Jakob disease, Bovine spongiform encephalopathy (“mad-cow disease,” from eating infected beef), and kuru (from eating brain previously infected with the disease) — all those are neurological disorders that are invariably fatal.

Since the structure of our proteins is ultimately determined by our genes, genetic variation could result in proteins that are less stable, or less able to function properly, and thereby cause disease (or a greater propensity for disease). Indeed, a single nucleotide mutation may have caused the protein misfolding disorders mentioned above. In addition, loss of function, or the acquisition of a new and undesirable function, could result in a severe disorder.

An example of a single nucleotide mutation that results in disease is sickle cell anemia. This disease is not caused by misfolding or by the loss of a vital function, but by the serendipitous aggregation of molecules. Sickle cell anemia is caused by the substitution of a valine (a hydrophobic amino acid, that is, one that prefers not to be in water) for a glutamic acid (a hydrophilic amino acid, that is, one that prefers to be in water) in the beta chain of the tetrameric hemoglobin in our blood. The substitution causes the hemoglobin molecules to stick together and form fibers, and those fibers cause the deformation (in the form of a sickle, hence the name) of the red blood cells which then clog the small blood vessels, leading to inflammation, pain, and, if untreated, early death.

There is nothing in this world that is all (and always) good. Proteins are no exception.

* * *

Eduardo A. Padlan was a research physicist at the US National Institutes of Health until his retirement in 2000. He serves as an adjunct professor in the Marine Science Institute, University of the Philippines Diliman, and is a corresponding member of the NAST. He may be contacted at [email protected].