The many functions of the endoplasmic reticulum chaperones and folding enzymes

Abstract

Endoplasmic reticulum (ER) is an essential sub-cellular compartment of the eukaryotic cell performing many diverse functions essential for the cell and the whole organism. ER molecular chaperones and folding enzymes are multidomain proteins that are designed to support nascent proteins entering ER lumen to achieve their native conformation, mediate post-translational modification, prevent misfolded protein aggregation, and facilitate exit from the ER. Typically the role of ER chaperones expands beyond protein folding. Here, we illustrate the multifunctional nature of many ER associated molecular chaperones and folding enzymes and unique functional overlap of these proteins all designed to support the many functions of the ER membrane. V C 2014 IUBMB Life, 66(5): [318][319][320][321][322][323][324][325][326] 2014

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

“…ER stress, which severely impairs protein folding, can be induced by different physiological and pathological conditions20, as well as by a number of compounds of synthetic or natural origins2122. Cells react to ER stress with an initial defensive process, the so called unfolded protein response (UPR), aimed at restoring homeostasis by enhancing protein folding capacity23; however, in conditions of severe stress, misfolded proteins accumulate in the ER ultimately triggering a set of prodeath programs (the yin and yang principle)21. Three major proteins are known to act as stress sensors in the ER: double-stranded RNA-dependent protein kinase PKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6)24.…”

Endoplasmic Reticulum Malfunction in the Nervous System

“…Calnexin, calreticulin, and PDIA3 (a protein foldase that catalyzes the formation and correct isomerization of disulfide bonds and interacts with both calnexin and calreticulin), are the core components of the ER protein quality control system (Hebert and Molinari, 2007). Folding of most of non-glycosylated proteins is supported by BiP/GRP78, a protein that interacts with hydrophobic regions of newly synthesized proteins (Hebert and Molinari, 2007; Halperin et al, 2014). Other chaperons including GRP94, ERdj3, cyclophilin B, PDI, PDIA4, SDF2, and additional members of the PDI family proteins form large protein folding complexes that interact with misfolded and unfolded proteins (Hebert and Molinari, 2007; Halperin et al, 2014) to assist in their proper processing.…”

“…Folding of most of non-glycosylated proteins is supported by BiP/GRP78, a protein that interacts with hydrophobic regions of newly synthesized proteins (Hebert and Molinari, 2007; Halperin et al, 2014). Other chaperons including GRP94, ERdj3, cyclophilin B, PDI, PDIA4, SDF2, and additional members of the PDI family proteins form large protein folding complexes that interact with misfolded and unfolded proteins (Hebert and Molinari, 2007; Halperin et al, 2014) to assist in their proper processing. Moreover, a class of small molecules, termed proteostasis promoters (Vega et al, 2016), have been identified.…”

Enhanced salt tolerance in tomato plants constitutively expressing heat-shock protein in the endoplasmic reticulum

“…A variety of molecular chaperones and foldases are involved in this system (Brodsky and McCracken, 1999;Halperin et al, 2014). Molecular chaperones, such as the ER binding protein (BiP), help newly synthesized proteins to assume their correct conformations, or associate with unrecoverable proteins to prevent them from exiting the ER until they are digested (Gething, 1999).…”