Nature deciphers key regulators of cell growth

The mTOR protein plays a central role
in cell growth, proliferation, and survival.
Its activity varies
depending on the availability of nutrients and some growth factors, including hormones.
This protein has been linked to a variety of diseases, including cancer, where its activity is often increased
.
To better understand its patterns, a team from the University of Geneva (UNIGE), in collaboration with researchers from Martin Luther University (MLU) in Germany, has determined the structure of the SEA complex – a group of interdependent proteins – responsible for controlling mTOR
.
The discovery of this structure allows us to better understand how cells sense nutrient levels to regulate their growth
.

From yeast to humans, the mTOR protein (the mammalian target of rapamycin) is the central controller of
cell growth.
This protein responds to various signals in the cellular environment, such as nutrients and hormones, and regulates many essential cellular functions such as protein and lipid synthesis, energy produced by mitochondria, and organization
of cellular structures.
Disruption of mTOR activity is the cause of a variety of diseases, including diabetes, obesity, epilepsy, and various cancers
.

Two opposite functions in the same complex

The lab of Robbie Loewith, a professor in the Department of Molecular and Cell Biology at the Faculty of Science and director of the National Center for Chemical Biology Competence, is interested in the regulation of mTOR, specifically the SEA complex, which is a direct sensor of nutrients that control mTOR activity
.
The SEA complex consists of
8 proteins.
One part of the SEA complex (SEACIT) is involved in the inhibition of mTOR activity, while the other part (SEACAT) is involved in the activation
of mTOR activity.

In the absence of nutrients, the mTOR protein is blocked by the SEACIT subcomplex, thereby hindering
cell growth.
In contrast, in the presence of nutrients, the SEACAT subcomplex is thought to be able to inhibit the SEACIT subcomplex and thus no longer be able to block the mTOR protein
.
The central controller can exert its activating role in cell growth, for example, by stimulating the production
of proteins and lipids.
HOW SEACAT REGULATES SEACIT IS UNCLEAR
.

Determine the structure to understand the function

To determine the interactions between the proteins of the SEA complex and thus better understand how they work, the researchers set out to determine the structure of
the complex.
After biochemically separating the SEA complex from all other components in the cell, the scientists used techniques from UNIGE, UNIL, and EPFL's Dubocht Imaging Center to obtain its molecular structure
by cryo-electron microscopy (cryo-EM).

Lucas Tafur, a researcher in the Department of Molecular and Cell Biology and first author of the study, explains: "By freezing samples very quickly at -180°C, cryo-EM can obtain the structure of proteins in their original state, i.
e.
their functional three-dimensional form
.
"

SEACAT is necessary, but not sufficient

The biochemical activity
of the different components of this complex is then tested in the laboratory.
Although the SEACAT subcomplex exists in its active form (when nutrients are present), the researchers observed that the SEACIT subcomplex is still active and able to block mTOR
.
"This result is very unexpected because SEACAT has long been described as a direct inhibitor
of SEACIT.
THEREFORE, WE EXPECT SEACIT TO BE INACTIVE
WHEN ACTIVE SEACAT EXISTS.
Our findings suggest that SEACAT acts more as a scaffold for recruiting other regulatory proteins, so its presence is necessary but not sufficient for inhibition of SEACIT," explains Robbie Loewith
, the last author of the study.

Obtaining the structure of the SEA complex can highlight the missing link
in the mTOR regulatory cascade.
"Of course, we now need to identify unknown partners
related to this complex.
These new factors may prove to be therapeutic targets for tumors with increased mTOR activity," concludes
Lucas Tafur.