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The biological and chemical basis for tissue-selective amyloid disease
Department of Chemistry, Skaggs Institute of Chemical Biology, San Diego, CA 92037, United States, Third Department of Medicine, Shinshu University, School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Department of Chemistry, Skaggs Institute of Chemical Biology, San Diego, CA 92037, United States.
Dept. of Molecular and Cell Biology, Inst. Childhood and Neglected Dis., Scripps Research Institute, 10550 N. Torrey Pines Road, San Diego, CA 92037, United States.
Hammarström, P., Department of Chemistry, Skaggs Institute of Chemical Biology, San Diego, CA 92037, United States, IFM-Department of Chemistry, Linkoping University, 581 83 Linkoping, Sweden.
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2005 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 121, no 1, 73-85 p.Article in journal (Refereed) Published
Abstract [en]

Factors controlling the onset and progression of extracellular amyloid diseases remain largely unknown. Central to disease etiology is the efficiency of the endoplasmic reticulum (ER) machinery that targets destabilized mutant proteins for degradation and the enhanced tendency of these variants to aggregate if secreted. We demonstrate that mammalian cells secrete numerous transthyretin (TTR) disease-associated variants with wild-type efficiency in spite of compromised folding energetics. Only the most highly destabilized TTR variants are subjected to ER-associated degradation (ERAD) and then only in certain tissues, providing insight into tissue selective amyloidosis. Rather than a "quality control" standard based on wild-type stability, we find that ER-assisted folding (ERAF), based on global protein energetics, determines the extent of export. We propose that ERAF (influenced by the energetics of the protein fold, chaperone enzyme distributions, and metabolite chaperones) in competition with ERAD defines the unique secretory aptitude of each tissue. Copyright ©2005 by Elsevier Inc.

Place, publisher, year, edition, pages
2005. Vol. 121, no 1, 73-85 p.
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Natural Sciences
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URN: urn:nbn:se:liu:diva-45468DOI: 10.1016/j.cell.2005.01.018OAI: oai:DiVA.org:liu-45468DiVA: diva2:266364
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13

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