Abstract:
: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.
journal_name
Celljournal_title
Cellauthors
Sekijima Y,Wiseman RL,Matteson J,Hammarström P,Miller SR,Sawkar AR,Balch WE,Kelly JWdoi
10.1016/j.cell.2005.01.018subject
Has Abstractpub_date
2005-04-08 00:00:00pages
73-85issue
1eissn
0092-8674issn
1097-4172pii
S0092-8674(05)00092-9journal_volume
121pub_type
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