Evolution of growth factor signaling to the TSC complex to regulate mTORC1

Area of Science:

• Cellular biology
• Molecular biology
• Biochemistry

Background:

• The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a central regulator of cellular growth, integrating signals from nutrients, energy status, and growth factors.
• mTORC1 activation leads to the phosphorylation of downstream substrates, promoting biomass accumulation and cell growth.
• The tuberous sclerosis complex (TSC) protein complex, particularly its TSC2 subunit, acts as a conserved brake on mTORC1 activation.

Purpose of the Study:

• To investigate the structural and evolutionary basis of mTORC1 regulation by growth factors through the TSC protein complex.
• To understand how upstream signals converge on TSC2 to modulate mTORC1 activity and cell growth.
• To explore the role of unstructured loops in TSC2's regulatory function and their evolutionary significance.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to study the structure of the TSC protein complex.
• Analysis of evolutionary conservation and disease-associated mutations in TSC2.
• Integration of structural data with knowledge of upstream signaling pathways.

Main Results:

• Phosphorylation sites regulating TSC2 function are located in unstructured loops outside the evolutionarily conserved core structure.
• These regulatory loops evolved with metazoans, coinciding with the emergence of complex body plans and diverse cell types.
• The unstructured loops of TSC2 lack disease-associated mutations, suggesting they are sites of evolutionary adaptation.

Conclusions:

• The evolution of unstructured regulatory loops in TSC2 enabled the integration of diverse growth factor signals to control mTORC1.
• This regulatory mechanism likely co-evolved with multicellularity to coordinate cell growth and metabolism across tissues.
• The plasticity of these loops suggests they are key drivers of adaptive changes in cell growth regulation.