ERchaperoner

ERchaperoner refers to a class of endoplasmic reticulum–resident molecular chaperones that assist in the folding, assembly, and quality control of secretory and membrane proteins within the ER. These proteins help nascent polypeptides achieve correct conformations, prevent aggregation of exposed hydrophobic regions, and facilitate proper disulfide bond formation and glycoprotein maturation. Many ERchaperoners function as holdases, binding substrates without consuming ATP, while others are ATP-dependent remodelers. They often operate in concert with established ER quality control pathways such as the calnexin/calreticulin cycle and with protein disulfide isomerases.

Localization and structure: Most ERchaperoners reside in the ER lumen; some are membrane-anchored with luminal domains that bind substrates. They commonly form dynamic complexes with co-chaperones and client proteins, displaying diverse substrate specificities.

Biological role: ERchaperoners are essential for efficient protein folding in the secretory pathway and for maintaining ER proteostasis. In cases of folding stress, they participate in unfolded protein response signaling and help guide irreparably misfolded proteins toward ER-associated degradation.

Evolution and examples: The concept encompasses canonical ER chaperone families, including BiP/GRP78, calnexin, calreticulin, and the protein disulfide isomerase family, which all contribute to ER quality control. The term emphasizes the shared chaperone function rather than a single genetic locus.

Clinical relevance: Altered ER chaperone activity has been linked to diseases featuring proteostasis imbalance, such as cystic fibrosis, certain diabetes forms, and neurodegenerative disorders. Modulation of ERchaperoner activity is a subject of therapeutic research.

Research and methods: Studying ERchaperoners employs co-immunoprecipitation, mass spectrometry, genetic knockdown or knockout, and structural techniques like cryo-electron microscopy and X-ray crystallography.

See also: Endoplasmic reticulum, Molecular chaperone, Protein folding, ERAD, Unfolded protein response.