Thousands of proteins depend on their tails to locate themselves in cell membranes and carry out their essential functions. Changes in the tails can lead to rare genetic diseases
The lipid envelopes that surround every living cell – membranes – are vibrant environments that host countless biological processes; they separate the cell from its environment and divide it into compartments, are responsible for metabolism, energy production, the transmission of messages between the cell and its environment, and more. Most of these processes are carried out by membrane proteins, that is, proteins that are produced in the cell and woven into those lipid envelopes. In a new study, the findings of which were recently published in the scientific journal Nature Communications., reveals Dr.'s group Nir Ploman from the Weizmann Institute of Science that the ability of thousands of proteins to successfully locate in the membrane and carry out their functions depends on their "tails," and that changes in the tails may lead to rare genetic diseases in humans.
While some membrane proteins cross the membrane only once, there is a significant group of proteins that cross it several times – similar to sewing thread woven into a piece of fabric. These proteins are made up of three components: helices located inside the membrane, loops that connect the helices, and tails – protein “thread ends” located before the first helix and after the last helix. The “sewing machine” mechanism that weaves most protein helices in the membrane was deciphered decades ago. As part of this mechanism, the ribosome – the cell’s protein-production factory – is attached to the membrane, and each time a helix is pushed off its “production line” due to the creation of the next helix in the chain, the “sewing machine” grabs it and “weaves” it into the membrane. The problem with the mechanism may arise in the last row, when the last helix remains stuck in the pipeline without being accessible to the sewing machine; If this helix fails to weave into the cell membrane, the entire protein will not function.
In the new study, led by Dr. Ilya Kalinin and Dr. Hadas Peled-Zehavi from Dr. Ploman's group in the Department of Biomolecular Sciences at the Institute, the scientists attempted to trace the evolutionary solution to the last helix problem. Some proteins have an "innate" solution - their tail is long enough, so that when it is created, the last helix is pushed off the assembly line and is long enough to be woven into the membrane. In contrast, there are many proteins that were not so fortunate - about 1,400 proteins in humans - and they simply have a tail that is too short.
We can discover mutations that cause diseases
The scientists showed in the study that the short tails had evolved to have a property of repelling water and a strong attraction to fat (hydrophobicity). This property could have helped them cross from the inside of the lipid membrane to the outside, thus positioning the last helix inside the membrane. However, due to the thickness of the lipid membrane, the increase in hydrophobicity is not sufficient on its own and an additional mechanism is required to help the tails cross the membranes. To identify the mechanism, the scientists silenced one by one systems that might be involved in the process and identified that damage to a protein called YidC led to a failure to position the last helix in the membrane.
The discovery of YidC revealed why the short tails became hydrophobic during evolution: Unlike the "sewing machine" mechanism that transports segments through the membrane in a non-selective manner through a channel that allows them to cross the membrane, YidC constricts a specific region of the thick lipid membrane, thus helping only segments that are already inherently hydrophobic to cross it more easily. In this way, the last helix problem was solved.
These discoveries led scientists to investigate whether problems with the short tails explain rare genetic diseases in humans. Using databases that include the results of genetic sequencing of patients, the scientists identified five genetic diseases caused by mutations in which the short tail loses its hydrophobicity, including a rare genetic defect associated with epilepsy and another associated with an inflammatory syndrome. The scientists were able to trace the mechanism of the two diseases described and noticed that in both cases the last helix of the proteins failed to weave itself into the membrane, and therefore the proteins remained dysfunctional. These proteins, which were supposed to be located in the membrane of an important organelle in the cell, did not reach it and instead ended up in another organelle that processes damaged proteins. "There are thousands of mutations in membrane proteins that cause disease in humans, and most of them we don't understand," says Dr. Plowman. "If we discover which sequences in proteins are important for their insertion into the membrane and their function, as we discovered with the short tails, we can understand mysterious genetic diseases and seek treatment for them."
Alon Barshef, Shai Tamari, Yarden Weiss and Dr. Rinat Nevo from the Institute's Department of Biomolecular Sciences also participated in the study.
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