Two opposing functions in the same complex.
The lab of Robbie Loewith, Professor in the Department of Cellular and molecular Biology at the UNIGE Faculty of Science and director of the National Center for Competence in Research in Chemical Biology, is interested in the regulation of mTOR, and in particular in the SEA complex, which is the direct sensor of nutrients and which controls the activity of mTOR. The SEA complex is composed of 8 proteins. One part of the SEA complex (SEACIT) is associated with the inhibition of mTOR activity, while the other part (SEACAT) is involved in its activation.
In the lack of nutrients, the mTOR protein is obstructed by the SEACIT subcomplex, and cell growth is thus avoided. In contrast, in the presence of nutrients, the SEACAT subcomplex is thought to hinder the SEACIT subcomplex, which can no longer obstruct the mTOR protein.
Identifying structure to comprehend the function.
To identify the interactions between the proteins of the SEA complex, and therefore better understand how they work, the scientists set out to figure out the structure of this complex. After biochemically separating the SEA complex from all of the other parts in the cell, the researchers used the technologies of the Dubochet Center for Imaging of UNIGE, UNIL, and EPFL to acquire its molecular structure by cryo-electron microscopy (cryo-EM).
” By freezing the samples very rapidly at -180 ° C, cryo-EM permits to acquire the structure of the proteins in their original state, i.e. in their functional three-dimensional form,” explains Lucas Tafur, a scientist in the Department of Cellular and molecular Biology and first author of the research study.
SEACAT is needed but not adequate.
The biochemical activities of the various components of the complex were then checked in the lab. Regardless of the SEACAT subcomplex remaining in an active kind (as when in the existence of nutrients), the researchers observed that the SEACIT subcomplex is still active and capable of blocking mTOR.
” This result is really unanticipated because SEACAT has long been referred to as the direct inhibitor of SEACIT. We, for that reason, anticipated SEACIT to be non-active in the presence of active SEACAT. Our outcomes show that SEACAT acts more as a scaffold for the recruitment of other regulative proteins and that its existence is, for that reason, essential however not enough for the inhibition of SEACIT,” explains Robbie Loewith, the last author of the research study.
Obtaining the structure of the SEA complex has permitted highlighting missing links in the mTOR regulatory waterfall. “Obviously, we now need to identify the as-yet unidentified partners that relate to this complex. These brand-new factors could show to be restorative targets for growths where mTOR activity is exacerbated,” concludes Lucas Tafur.
Referral: “Cryo-EM structure of the SEA complex” by Lucas Tafur, Kerstin Hinterndorfer, Caroline Gabus, Chiara Lamanna, Ariane Bergmann, Yashar Sadian, Farzad Hamdi, Fotis L. Kyrilis, Panagiotis L. Kastritis and Robbie Loewith, 26 October 2022, Nature.DOI: 10.1038/ s41586-022-05370-0.
A group from the University of Geneva (UNIGE), in collaboration with scientists from the Martin Luther University (MLU) of Halle-Wittenberg in Germany, and the just recently inaugurated Dubochet Center for Imaging (UNIGE-UNIL-EPFL), has recognized the structure of the SEA complex, an interdependent set of proteins responsible for managing mTOR. The lab of Robbie Loewith, Professor in the Department of Cellular and molecular Biology at the UNIGE Faculty of Science and director of the National Center for Competence in Research in Chemical Biology, is interested in the policy of mTOR, and in particular in the SEA complex, which is the direct sensing unit of nutrients and which controls the activity of mTOR. The SEA complex is made up of eight proteins. One part of the SEA complex (SEACIT) is involved in the inhibition of mTOR activity, while the other part (SEACAT) is involved in its activation.
To figure out the interactions in between the proteins of the SEA complex, and hence better understand how they work, the researchers set out to figure out the structure of this complex.
The SEA complex is composed of a cage-like core (SEACAT, blue) that controls the activity of the wings (SEACIT, white and intense). Credit: © Ciencia Graficada
A UNIGE team has actually found the structure of a protein complex that controls the activity of the significant growth regulator.
The mTOR protein plays a central role in cell growth, survival, and proliferation. Its activity is impacted by the accessibility of nutrients along with numerous development aspects such as hormones. This protein has actually been connected to a number of diseases, consisting of cancer, where its activity often increases.
A group from the University of Geneva (UNIGE), in collaboration with scientists from the Martin Luther University (MLU) of Halle-Wittenberg in Germany, and the just recently inaugurated Dubochet Center for Imaging (UNIGE-UNIL-EPFL), has recognized the structure of the SEA complex, an interdependent set of proteins accountable for managing mTOR. The finding of this structure offers a much better understanding of how cells perceive nutrient levels in order to manage their growth. The study was recently released in the journal Nature..
From yeast to humans, the mTOR protein (mammalian target of rapamycin) is the central controller of cell development. This protein reacts to ecological cues such as hormonal agents and nutrients and controls a number of key cellular functions such as protein and lipid synthesis, energy production by mitochondria, and cell structure organization. mTOR activity interruptions are the source of numerous conditions, including diabetes, weight problems, epilepsy, and a number of kinds of cancer.
