Protein form and function

Whitehead Institute scientists have at last answered the long-standing question of how the growth-regulating pathway known as mechanistic target of rapamycin complex 1 (mTORC1) detects the presence of the amino acid leucine—itself a key player in modulating muscle growth, appetite, and insulin secretion.

Countering the prevailing theory that cellular hydrogen peroxide signaling is broad and non-specific, Whitehead Institute scientists have discovered that this reactive oxygen species (ROS) in fact triggers a distinct signal transduction cascade under control of the mitochondrial respiratory chain—the Syk pathway—that regulates transcription, translation, metabolism, and the cell cycle in diverse cell types. Hydrogen peroxide and other ROS mediate cellular responses in aging and myriad common chronic diseases, including diabetes, heart disease, stroke, cancer, and neurodegeneration. Understanding how these signals function may point to new therapy targets for these conditions.

A protein known to play a role in transporting the molecular contents of normal cells into and out of various intracellular compartments can also turn such cells cancerous by stimulating a key growth-control pathway.

Upsetting the balance between protein synthesis, misfolding, and degradation drives cancer and neurodegeneration. Recent cancer treatments take advantage of this knowledge with a class of drugs that block protein degradation, known as proteasome inhibitors. Widespread resistance to these drugs limits their success, but Whitehead researchers have discovered a potential Achilles heel in resistance. With such understandings researchers may be able to target malignancy broadly, and more effectively.

By teasing apart the structure of an enzyme vital to the parasites that cause toxoplasmosis and malaria, Whitehead Institute scientists have identified a potentially ‘drugable’ target that could prevent parasites from entering and exiting host cells.

According to Whitehead Institute researchers, cells with malfunctioning mitochondria are unable to proliferate due to a shortage of the amino acid aspartate, not because of an energy crisis, as was once thought. Mitochondrial dysfunction plays a role in a host of relatively rare disorders as well as neurodegenerative disorders, including Parkinson’s disease.

Scientists in the lab of Whitehead Institute Member David Sabatini have for the first time identified a protein that appears to be a nutrient sensor for the key growth-regulating mTORC1 metabolic pathway. 

Scientists have long theorized that the way in which the roughly three meters of DNA in a human cell is packaged to fit within a nuclear space just six microns wide, affects gene expression. Now, Whitehead Institute researchers present the first evidence that DNA structure does indeed have such effects—in this case finding a link between chromosome structure and the expression and repression of key genes.

Cells rely on the mechanistic target of rapamycin complex 1 (mTORC1) pathway—which senses the availability of nutrients—to coordinate their growth with existing environmental conditions. The lab of Whitehead Member David Sabatini has identified a family of proteins that negatively regulate the branch upstream of mTORC1 that senses amino acids, the building blocks of proteins.

Long associated with enabling the proliferation of cancer cells, the ancient cellular survival response regulated by Heat-Shock Factor 1 (HSF1) can also turn neighboring cells in their environment into co-conspirators that support malignant progression and metastasis.