Molecular Origami: Protein folding and misfolding in health and disease

Abstract

Folding within the crowded cellular milieu often requires assistance from molecular chaperones, which prevent inappropriate interactions leading to aggregation and toxicity. The contribution of individual chaperones to protein folding and quality control remain elusive. The accumulation of misfolded proteins in intracellular amyloid inclusions, typical of many neurodegenerative disorders including Huntington's and Prion Disease, is thought to arise upon failure of the cellular protein Quality Control (QC) mechanisms. Our work aims to understand the role of chaperones in folding and in the formation of misfolded protein inclusions in the eukaryotic cytosol. Recently, we identified two intracellular compartments for the sequestration of misfolded cytosolic proteins. Soluble ubiquitinated misfolded proteins accumulate in a juxtanuclear compartment where proteasomes are concentrated. In contrast, terminally aggregated proteins are sequestered in a perivacuolar inclusion. Strikingly, disease‐associated Huntingtin and prion proteins are preferentially directed to the perivacuolar compartment. Our findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease.