Distinct structural mechanisms drive gain-of-function activation of TMEM16E in gnathodiaphyseal dysplasia
This study reveals that the gnathodiaphyseal dysplasia-associated gain-of-function mutations G503E and R582I activate TMEM16E through distinct structural mechanisms—disrupting the TM3–TM4 interface and remodeling an extracellular loop network, respectively—despite their similar functional phenotypes.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Inside the cells of our bodies, a family of proteins acts as gatekeepers and mixers, responding to calcium signals to move ions and shuffle the fatty building blocks of cell membranes. One specific member of this family, known as TMEM16E, is vital for the health of our muscles and bones. When this protein works correctly, it helps repair damaged cell surfaces and ensures that new fats are distributed evenly across the membrane layers. However, when the instructions for building this protein are altered by genetic mutations, the consequences can be severe. Some changes cause muscles to weaken and waste away, while others lead to a rare condition called gnathodiaphyseal dysplasia, a disorder that causes the jaw and long bones to become brittle and prone to breaking. For years, scientists understood that these diseases were linked to the protein malfunctioning, but they did not know exactly how the protein worked in its normal state or how the specific mutations caused it to go haywire.
A team of researchers has now peered directly into the structure of this protein to solve that mystery. Using powerful imaging technology that freezes molecules in time to reveal their atomic shape, they mapped out the protein both when it is resting and when it is bound to calcium. They also examined two specific mutations that cause the bone disorder to see how they change the protein's shape. The results revealed that this protein behaves differently than its relatives. While other proteins in the same family must undergo a dramatic twisting and bending to turn on, this one is already prepped and ready. Its calcium-binding sites are formed even before calcium arrives, and the protein does not need to rearrange its internal parts to become active. Instead, the calcium simply binds to a spot that is already there, though the researchers found that even with high levels of calcium, one of the binding spots often remains only partially filled.
The most surprising discovery came when the scientists looked at the two mutations that cause the bone disease. Both mutations lead to the same dangerous outcome: the protein becomes permanently active, scrambling lipids and conducting ions even when it should be resting. It was long assumed that mutations causing similar diseases would break the protein in the same way. However, the researchers found that these two mutations act through completely different mechanical pathways. One mutation, located in a loop on the outside of the cell, disrupts a network of connections that holds the protein's outer loops in place. This disruption makes the calcium-binding site more attractive, causing the protein to grab onto calcium more tightly and stay active. The other mutation, located deeper within the protein's core, pushes apart two internal helices that usually hold the protein shut. This forces the protein into a shape that resembles an open, cross-like groove, allowing lipids to flip-flop across the membrane freely.
To confirm how these structural changes lead to activity, the researchers used computer simulations to watch the protein move over time. They observed that the mutation which pushes the internal helices apart allows the protein to settle into a stable, open state that is very similar to the active form of a different, well-known protein in the same family. In these simulations, the open groove allowed lipids to pass through, explaining why the mutation causes such a strong gain of function. In contrast, the other mutation did not force the protein into this open shape but instead kept it in a state where it was more likely to bind calcium and activate. These findings show that two different genetic errors can lead to the same disease by taking two distinct roads to the same destination. By understanding these separate mechanisms, scientists now have a clearer picture of how this protein functions and how it fails, which could eventually help in designing treatments that target the specific cause of the disease in each patient.
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