Abstract
Protein quality control in the early secretory pathway is a ubiquitous eukaryotic mechanism for adaptation to endoplasmic reticulum (ER) stress. An ER molecular chaperone, immunoglobulin heavy chain-binding protein (BiP), is one of the essential components in this process. BiP interacts with nascent proteins to facilitate their folding. BiP also plays an important role in preventing aggregation of misfolded proteins and regulating the ER stress response when cells suffer various injuries. BiP is a member of the 70-kDa heat shock protein (HSP70) family of molecular chaperones that resides in the ER. Interaction between BiP and unfolded proteins is mediated by a substrate-binding domain and a nucleotide-binding domain for ATPase activity, leading to protein folding and maturation. BiP also possesses a retrieval motif in its carboxyl terminal. When BiP is secreted from the ER, the Lys-Asp-Glu-Leu (KDEL) receptor in the post-ER compartments binds with the carboxyl terminal KDEL sequence of BiP and returns BiP to the ER via coat protein complex I (COPI) vesicular transport. Although yeast studies showed that BiP retrieval by the KDEL receptor is not essential in single cells, it is crucial for multicellular organisms, where some essential proteins require retrieval to facilitate folding and maturation. Experiments in knock-in mice expressing mutant BiP with the retrieval motif deleted revealed a unique role of BiP retrieval by the KDEL receptor in neuronal development and age-related neurodegeneration.
Highlights
The endoplasmic reticulum (ER) is the first organelle of the secretory pathway and plays an important role in synthesizing proteins and the lipid membrane
Nascent peptides bind to ER molecular chaperones such as immunoglobulin heavy chain-binding protein (BiP/GRP78), calnexin, calreticulin and protein disulfide isomerase present in the ER lumen, thereby escaping aggregation and degradation
Heterozygous mutant BiP mice live to adulthood, with no significant difference in life span compared to wild-type mice
Summary
The endoplasmic reticulum (ER) is the first organelle of the secretory pathway and plays an important role in synthesizing proteins and the lipid membrane. Nascent peptides bind to ER molecular chaperones such as immunoglobulin heavy chain-binding protein (BiP/GRP78), calnexin, calreticulin and protein disulfide isomerase present in the ER lumen, thereby escaping aggregation and degradation. These proteins are modified with sugar chains and disulfide bonds to form a three-dimensional structure and complexes with other protein subunits (Zhang et al, 1997). Immature (unfolded or misfolded) proteins are formed due to extrinsic insults (e.g., ischemia, malnutrition, hypoxia and toxic substances) or intrinsic insults (e.g., mutated sequence, missing subunits) They accumulate in the ER, inducing the ER stress response or unfolded protein response (UPR). When the level of unfolded proteins exceeds the adaptive capacity, intra- and extracellular protein aggregations form, resulting in cellular dysfunction and cell death (Walter and Ron, 2011; Figure 1)
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