title: The biological and chemical basis for tissue-selective amyloid disease.
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.
authors.affiliation: Department of Chemistry, The Skaggs Institute of Chemical Biology, The Skaggs Research Institute, 10550 N. Torrey Pines Road, BCC506, La Jolla, California 92037, USA.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sekijima
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
authors.forename: Jeanne
authors.initials: J
authors.lastname: Matteson
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
authors.forename: Sean R
authors.initials: SR
authors.lastname: Miller
authors.forename: Anu R
authors.initials: AR
authors.lastname: Sawkar
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000686:Amyloidosis / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000737:chemistry*; D006224:Cricetinae; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D009928:Organ Specificity; D011228:Prealbumin / Q000737:chemistry*; D017510:Protein Folding; D013974:Thyroxine / Q000737:chemistry
chemical_list: D018832:Molecular Chaperones; D011228:Prealbumin; D013974:Thyroxine