Paper ID: 261
Max Planck Institute of Biochemistry (Germany)
The past two decades have witnessed a paradigm shift in our understanding of cellular protein folding. While the three-dimensional structures of functional proteins are determined by their amino acid sequences, we now know that in the crowded environment of cells newly-synthesized polypeptides depend on molecular chaperone proteins to reach their folded states efficiently and at a biologically relevant time scale. Assistance of protein folding is provided by different types of chaperone which act to prevent misfolding and aggregation, often in an ATP-dependent mechanism. Once folded, many proteins continue to require chaperone surveillance to retain their functional states, especially under conditions of cell stress. Failure of the chaperone machinery to maintain proteostasis, i.e. the conformational integrity and balance of the cellular proteome, facilitates the manifestation of diseases in which proteins misfold and form toxic aggregates. These disorders include Parkinson’s, Huntington’s and Alzheimer’s disease.
We are using yeast as a model to study the mechanism and consequences of protein aggregation. A focus of ongoing research is on understanding ribosome quality control (RQC). Defects in RQC result in toxic aggregation of nascent polypeptides that stall during translation on ribosomes. These aggregates have features resembling those associated with neurodegenerative disease.
Balchin D, Hayer-Hartl M, Hartl FU. In vivo aspects of protein folding and quality control.
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