Ahmet S. Vakkasoglu
At some point in our lives, all humans have been infected by viruses. In most cases, the infection is taken care of by our internal immune system before we even notice we’ve been infected. In other cases, we fall ill for a couple of days and spend time in bed while our immune system takes its time to fight off the infection. In rare cases, serious viral infections can eventually kill us. This can happen in a couple of days, or can take several years. Ebola and Human Immunodeficiency Virus (HIV) infections are some well-known examples of such deadly infections.
The human immune system responds to viral infections in two ways. The first is the innate immune system. It is the first line of defense in our body and the only one that exists in many multi-cellular organisms. It involves certain kinds of immune cells that recognize pathogens. These cells immediately attack and ultimately destroy the infection-causing microbes. One may find the classical video showing a macrophage engulfing a bacterial cell interesting (https://www.youtube.com/watch?v=JnlULOjUhSQ). However, the innate immune system is not specific and does not form a memory against infections.
The second and more specific type of immune system is called the adaptive immune system. As the name suggests, it is specific and can build immunity against certain kinds of infection. Compared to the innate immune system, it is slower, but its high specificity makes it a powerful defense mechanism. The adaptive immune system is present only in jawed vertebrates, as it requires several macromolecular systems, which are found only in more complex organisms.
One of the main parts of these complex molecular systems forming the adaptive immunity is called the antigen processing. This refers to the presence of small particles on the cell surface. This process requires the transportation of these antigens from the inside to the outside surface of the cell. The plasma membrane of the cell is semi-permeable to chemicals and small molecules. Only small, uncharged, hydrophobic molecules can diffuse through these membranes. However, antigens are usually small pieces of proteins that are charged. Therefore, the transport of antigens through the plasma membrane is not an easy task. This difficult task is done by a special transporter, called the transporter associated with antigen processing (TAP).
In order to transport antigens across the membrane, TAP uses adenosine triphosphate (ATP) as its energy source. For almost a half century, scientists tried to understand how these molecules transport their substrates across membranes . Although biochemical studies have taught us a lot, there is still more to be discovered. Years of research resulted in different models that explain how TAP works and why it needs energy. A recent finding helped to shape the working model to its current form, while also explaining that very important question: why does TAP need energy?
The working model of membrane transport assumes that TAP has two main conformations . In one of the conformations, the antigen binding site is open to one side of the membrane. In the other conformation, the binding site is open to the other side of the membrane. This allows the antigen to be transported from one side of the membrane to the other. However, one major question this model raises is why TAP doesn't allow the antigen to leak back.
This would be a deadly issue if it was the case for the cell. We know that this does not happen, but we don’t know why it doesn’t happen. Scientists have been trying to tweak their models to fit a one-way transport mechanism.
The recent study mentioned above showed that TAP works in one direction only, confirming the predictions. The study also addressed why TAP needs energy, i.e., ATP hydrolysis. Energy is needed to ensure that the antigens do not leak back. This finding also makes sense when other transporters that do not need energy are considered, simply because they can work in both directions. In short, TAP uses energy only when it "swallows" the antigens to the other side of the membrane while making sure they don’t leak back.
The proper functioning of TAP is critical for human health. Genes encoding TAP have been shown to have nearly 100 single nucleotide polymorphisms (SNPs), the variations in the human genome. Some of these SNPs cause immune deficiencies in certain individuals or populations. These SNP studies further highlight the importance of TAP.
The story told above is taking place in our cells all the time. Even when we fall ill and rest in bed, the adaptive immune system and TAP fulfill their roles and help our body recover.
1. Jardetzky, O., Simple allosteric model for membrane pumps. Nature, 1966. 211(5052): p. 969-70.
2. Grossmann, N., et al., Mechanistic determinants of the directionality and energetics of active export by a heterodimeric ABC transporter. Nat Commun, 2014. 5: p. 5419.