Co‐ and Post‐Translational Protein Folding in the ER

Abstract

The biophysical rules that govern folding of small, single-domain proteins in dilute solutions are now quite well understood. The mechanisms underlying co-translational folding of multidomain and membrane-spanning proteins in complex cellular environments are often less clear. The endoplasmic reticulum (ER) produces a plethora of membrane and secretory proteins, which must fold and assemble correctly before ER exit -if these processes fail, misfolded species accumulate in the ER or are degraded. The ER differs from other cellular organelles in terms of the physicochemical environment and the variety of ER-specific protein modifications. Here, we review chaperone-assisted co-and post-translational folding and assembly in the ER and underline the influence of protein modifications on these processes. We emphasize how method development has helped advance the field by allowing researchers to monitor the progression of folding as it occurs inside living cells, while at the same time probing the intricate relationship between protein modifications during folding.

The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK)

“…During ERAD, misfolded protein substrates are recognized by molecular chaperones such as Hsp70 and ubiquitinated by E3 ubiquitin ligases that are ER associated (2,4). After the acquisition of a polyubiquitin tag, the ERAD substrate is retrotranslocated from the ER in an ATP-dependent process that utilizes the AAA-ATPase, Cdc48 (in yeast) or p97 (in mammals).…”

“…_______________________________________ Protein quality control allows cells in all organisms to survive proteotoxic stresses and fine-tune their proteome in response to environmental changes (1). Significant recent work has elucidated in great detail how protein quality control pathways operate in the cytoplasm and in the endoplasmic reticulum (ER) (2)(3)(4). Common to both pathways is the delivery of substrates to the cytoplasmic proteasome, which selectively degrades ubiquitinated and misfolded protein substrates (5).…”

Machinery that guides immunity

“…Wilson's proposal requires electrons that have sufficiently high initial energies to overcome this force. It is now known that cosmic rays irradiate the atmosphere and produce such electrons, which multiply in thunderclouds to form an avalanche of highenergy electrons 4 . However, in the mid-1920s, cosmic rays were extremely mysterious and thought to be of terrestrial origin 5 .…”

“…These include: TAP1 and TAP2, which form a heterodimer known simply as TAP, and which move peptides of preferred length and sequence into the ER; tapasin, which interacts with TAP; and ERp57, which is needed for tapasin to function in the assembly of MHC class I products. Calreticulin, a protein involved in the sensing of nascent glycoproteins 4 , also forms part of the PLC, where it recruits MHC class I molecules to the complex.…”

“…In the ER, TAPBPR associates with an enzyme called UDP glucose glycoprotein glycosyltransferase, which, in conjunction with other ER-resident enzymes, acts as a timer for the engagement and release of MHC class I molecules by the calnexin-calreticulin cycle (which controls glycoprotein maturation in the ER; ref. 4). Possible discrepancies between the way in which the calnexin-calreticulin cycle in the ER controls folding and assembly of MHC class I molecules, and TAPBPR-imposed quality control elsewhere in the cell, can now be addressed in greater detail.…”