Sae-Hun Park, Ph.D.
In humans, about 25,000 of different proteins are responsible for most aspects of biological function and to attain their functionality, the majority of proteins must fold into well-defined three-dimensional structures and maintain their structural stability and flexibility throughout the lifetime. However, nascent proteins synthesized inside the cell are constantly at risk of attaining non-native conformations that prevent them from functioning properly and/or cause them to aggregate. Therefore, the cells have a collective ability to regulate well balanced the production and elimination of abnormal protein for entire proteomic integrity. To circumvent the protein misfolding problems, cells have evolved with robust and interconnected compartmental protein quality control (PQC) systems. PQC systems consist of chaperones, proteolytic systems, and other accessory proteins. For example, under stress conditions, molecular chaperones can either assist in the refolding of misfolded proteins or transfer misfolded proteins to the ubiquitin-proteasome system. When folding intermediate and misfolded protein are off-pathways, they tend to accumulate as protein aggregates which could be degraded through the autophagy pathway with the help of chaperones.
These mechanisms must be tightly regulated to maintain proper protein homeostasis or proteostasis. Failure of proteostasis control has been associated with a number of age-onset of neurodegenerative diseases like Huntington’s, Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS). We assume that protein quality control is the most important means of clearance of misfolded proteins from the cell interior.
We have reported several important discoveries for providing evidence of chaperones participating equally in folding and degradation of misfolded proteins and how proteins aggregates disrupt cellular waste disposal by sequestering chaperones through the ubiquitin-proteasome system. we are investigating how the nucleus copes with misfolded/aggregation-prone proteins and identify proteins that help in maintaining nuclear homeostasis. Further studies shall now show whether and to what extent these fundamental processes play a role in the pathogenic protein plaques.
We also want to investigate whether and how distinct compartments of protein quality control communicate and influence each other by using a yeast system (an excellent model organism for biochemical and genetic analysis). We have focused on the cross-talking of protein quality controls between ribosome-associated quality control (RQC) and other protein quality controls, and the biological relevance of RQC deficiency in proteostasis.
People involved in the work
Lucas Cairo, PhD
Chandhuru Jagadeesan, Ph.D. student