quarta-feira, 19 de janeiro de 2011
Amilóide - Artigo da Cell
Amyloid-like Aggregates Sequester Numerous Metastable Proteins with Essential Cellular FunctionsSummaryComments
Cell, Volume 144, Issue 1, 67-78, 7 January 2011
Heidi Olzscha, Sonya M. Schermann, Andreas C. Woerner, Stefan Pinkert, Michael H. Hecht, Gian G. Tartaglia, Michele Vendruscolo, Manajit Hayer-Hartl, F. Ulrich Hartl, R. Martin VabulasSee AffiliationsHint: Rollover Authors and Affiliations Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82159 Martinsried, Germany Department of Chemistry, Princeton University, Princeton, NJ 08544, USA Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK Corresponding author These authors contributed equally to this work Present address: Bioinformatics & Genomics Program, CRG Centre for Genomic Regulation, Dr. Aiguader 88, Barcelona 08003, Spain
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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