Closer to deciphering TOR, the molecular machinery that makes humans and yeast grow

The name might sound like a Nordic god, but it is actually the molecular machinery that allows many different species to eat and grow: fungi, plants, whales, humans, flies… It is the mighty TOR protein. An expedition to Easter Island half a century ago led to its discovery, and today it remains the subject of intense study. Lucas Tafur, a researcher at the National Cancer Research Centre (CNIO), has just solved the structure of one of the molecular switches that regulate this protein.

This breakthrough will help us understand why cancer and other diseases appear when this important protein does not function. These findings have been published in the journal Nature Structural & Molecular Biology.

“All cells have mechanisms to perceive how many nutrients are available, and to transmit that information to other proteins that regulate cell growth,” Tafur explains. “In the absence of nutrients, TOR is inhibited, and the cell slows down its growth. When there are plenty of resources, such as amino acids or glucose, the opposite happens: TOR activates and promotes cell growth and proliferation.”

This is broadly how TOR works, but it is important to understand the mechanics of this process in much more detail. A solid understanding of how the activity of TOR is regulated, for example, would open up pathways to design new drugs.

We now know that nutrients do not regulate TOR directly, but instead through other protein complexes. Because TOR, also known as mTOR in mammals, actually acts as part of two large complexes of several assembled proteins, TORC1 and TORC2.

“A drug that interferes with the overall activity of TOR has lots of side effects,” explains Tafur, head of the Structural Mechanisms of Cell Growth Group at CNIO. “But if we understand in detail the machinery that regulates TOR, we can find a way to intervene more selectively.”

A ‘molecular kit’ so living beings can eat and grow

If proteins are the molecular machinery that makes cells work, TOR is one of the central gears in the system. And it is present in many different organisms because it solves a common problem for all of them: detecting available nutrients to decide whether there are resources to grow or not. TOR is the equivalent of a standard molecular toolkit that performs this task very well, and as a result, evolution has preserved it over billions of years.

In primates and in fungi; in birds and insects; in rose bushes and hake, TOR is the system that decides whether there is food within reach, and therefore growth is possible, or whether there is not, and it is time to conserve energy.

Tafur is investigating TOR in yeast. He is in fact the only scientist at CNIO working with this microorganism, Saccharomyces cerevisiae, conveniently housed in containers in his laboratory. The similarity of TOR components between humans and yeast means that findings in one system can help understand how TOR works in the other.

Putting together a 3D puzzle without having the pieces

TOR is the acronym for Target of Rapamycin, which refers to the molecule to which rapamycin binds, a compound discovered in 1975 in samples collected on an expedition to Easter Island. Rapamycin has immunosuppressive and anticancer properties and was already used in several drugs – for example, to prevent transplant rejection – before the discovery was made in the 1990s, using yeast, that TOR is actually its target.

The challenge of trying to explain how TOR works is like putting together an extremely difficult microscopic three-dimensional puzzle, with the added difficulty that the shape of all the pieces is not even known. That is precisely the first challenge: to determine the structure of each tiny gear.

In recent years, research groups around the world have been making progress on this challenge. They are all using cryo-electron microscopy, a technique that freezes samples at temperatures close to that of liquid nitrogen, −196 °C, and obtains 3D images at near-atomic resolution of molecular complexes. With this technique, Tafur has solved the structure of a key regulator of TOR: the SEA complex (also known as GATOR).

SEA, the great regulator of TOR

 “SEA is a huge complex that integrates many signals at the same time,” says Tafur. “In the cell, everything related to nutrients passes through that complex: amino acids, cholesterol, glucose… And the truth is that we don’t really know how all the signals integrate.”

The new finding published in Nature Structural & Molecular Biology reveals two new aspects about the functioning of SEA. The first is that SEA does not actually regulate TOR in the way it was previously thought.

The complex has two parts, and it was assumed that the activity of one of them regulated the activity of the other through a system that Tafur’s study rejects. “We are seeing that this concept is not entirely true. There is no subdivision within the complex in which one part blocks the other. Rather, it functions as a whole.”

A switch that quickly activates TOR

Another important result is that a specific mutation in an amino acid is enough for the system to stop working. “This activity is like a switch, which is needed not only to inhibit TOR – as it has always been thought – but also to activate it quickly,” says Tafur.

This discovery will help us understand why, when this important protein does not function properly, cancer and other diseases appear, and eventually it may also open up pathways to selectively modulate its action. And it also reminds us of how much we share with other living beings.

About the National Cancer Research Centre (CNIO)

The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.