The Protein Disulfide Isomerase Family: from proteostasis to pathogenesis

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 2; p. 129338
• Main Authors: Matsusaki, Motonori, Kanemura, Shingo, Kinoshita, Misaki, Lee, Young-Ho, Inaba, Kenji, Okumura, Masaki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2020
• Subjects: Chaperoning; endoplasmic reticulum; ER-associated degradation; homeostasis; mammals; Oxidative protein folding; Pathogenesis; pathophysiology; PDI; protein disulfide-isomerase; protein folding; proteins; Proteostasis; structural biology; αSN; TAP; Proteostasis; CRT; Oxidative protein folding; Pathogenesis; PLC; AFM; ALS; BiP; PERK; CNX; Aβ; ERdj5; ERdj4; Hsp70; PDI; SNO; UPR; IRE1; MD; MHC-I; PDIs; Trx; BPTI; cryo-EM; β2m; XBP1; AD; PrD; EDEM1; ER-associated degradation; ER; SAXS; SOD1; eIF2α; ERAD; BPA; NMR; Chaperoning; PD; TDP-43; ITC; HC; ATF6; RNase A
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.04.003

In mammalian cells, nearly one-third of proteins are inserted into the endoplasmic reticulum (ER), where they undergo oxidative folding and chaperoning assisted by approximately 20 members of the protein disulfide isomerase family (PDIs). PDIs consist of multiple thioredoxin-like domains and recognize a wide variety of proteins via highly conserved interdomain flexibility. Although PDIs have been studied intensely for almost 50 years, exactly how they maintain protein homeostasis in the ER remains unknown, and is important not only for fundamental biological understanding but also for protein misfolding- and aggregation-related pathophysiology. Herein, we review recent advances in structural biology and biophysical approaches that explore the underlying mechanism by which PDIs fulfil their distinct functions to promote productive protein folding and scavenge misfolded proteins in the ER, the primary factory for efficient production of the secretome. [Display omitted] •Oxidative folding and chaperoning in the ER are assisted by ~20 PDI family members.•PDIs recognize and act on clients via conserved interdomain flexibility.•Exactly how PDIs maintain protein homeostasis remains to be uncovered.•Aberrant PDI activity leads to protein misfolding- and aggregation-related pathology.