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Unraveling protein quality control mechanisms by the ubiquitin system

Research4e.jpgApart from water, proteins make up the second most abundant component of our bodies (60 – 70% water, approximately 20% protein). Indeed, proteins perform a wide range of biological functions, such as through enzymes or shaping of our bodies. Proteins are synthesized at ribosomes based on the information in mRNA by connecting 20 types of amino acids into a string-like structure. A protein only becomes functional upon proper folding of this “string” into a proper structure.

It is estimated that a significant amount of newly synthesized proteins (it has been reported to be between 10 – 30%) fail at folding into their native structure and are thus defective. In addition, even properly folded proteins are constantly exposed to structural abnormality promoting stresses (e.g. heat, UV radiation, low oxygen, reactive oxygen species). However, such misfolded proteins are almost undetectable in cells. This is because of a “protein quality control system.” The ubiquitin proteasome system is a major component of the protein quality control system, and prevents the accumulation of defective proteins through the recognition, degradation, and removal of misfolded proteins.

When the amount of misfolded proteins produced exceeds the capacity of cellular protein quality control systems, in particular in neurons with the formation of protein aggregates, neurons undergo cell death, and misfolded proteins becomes a cause of neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease). In addition, even if the amount of defective proteins produced is normal, a decline in the activity of protein quality control systems makes people susceptible to neurodegeneration.

While it is known that the ubqiquitin system and the proteasome play important roles in the clearance of misfolded proteins, it remains unknown how misfolded proteins are distinguished from native proteins, and how only the former are targeted for degradation. We aim to unravel the molecular mechanisms behind the degradation of cellular misfolded proteins.