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. 2011 Jan 7;144(1):67-78.
doi: 10.1016/j.cell.2010.11.050.

Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

Heidi Olzscha  1 , Sonya M Schermann, Andreas C Woerner, Stefan Pinkert, Michael H Hecht, Gian G Tartaglia, Michele Vendruscolo, Manajit Hayer-Hartl, F Ulrich Hartl, R Martin Vabulas
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Free article

Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions

Heidi Olzscha et al. Cell. .
Free article

Abstract

Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial β sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation _targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions.

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