Protein Folding and Modification in the Mammalian Endoplasmic Reticulum

Abstract

Analysis of the human genome reveals that approximately a third of all open reading frames code for proteins that enter the endoplasmic reticulum (ER), demonstrating the importance of this organelle for global protein maturation. The path taken by a polypeptide through the secretory pathway starts with its translocation across or into the ER membrane. It then must fold and be modified correctly in the ER before being transported via the Golgi apparatus to the cell surface or another destination. Being physically segregated from the cytosol means that the ER lumen has a distinct folding environment. It contains much of the machinery for fulfilling the task of protein production, including complex pathways for folding, assembly, modification, quality control, and recycling. Importantly, the compartmentalization means that several modifications that do not occur in the cytosol, such as glycosylation and extensive disulfide bond formation, can occur to secreted proteins to enhance their stability before their exposure to the extracellular milieu. How these various machineries interact during the normal pathway of folding and protein secretion is the subject of this review.

The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins

“…S8), which is a critical test for their structural integrity (33). On the basis of these improved biophysical characteristics, our mutants were engineered into the C L domain in the context of a full-length κLC and assessed for their ability to exert their advantageous characteristics in mammalian cells, where the accuracy of antibody folding and assembly are monitored by quality control processes in the endoplasmic reticulum (ER) (34). We expressed the different LC variants, comprising mutants M1, M2, or M1+2, either alone or together with IgG HCs (γHCs) in COS-1 cells (35), and compared them with wild-type κLC.…”

Characterization of the Dimerization Interface of Membrane Type 4 (MT4)-Matrix Metalloproteinase

“…N-Linked glycosylation of MT4-MMP may contribute to the stability of the dimers by promoting noncovalent interactions. Alternatively, N-glycans may play a role during the process of MT4-MMP folding and generation of disulfide bonds (34). However, 3 Q.…”

A Viral Deubiquitylating Enzyme Restores Dislocation of Substrates from the Endoplasmic Reticulum (ER) in Semi-intact Cells

“…In eukaryotic cells, a fraction of newly synthesized proteins misfolds early during their biogenesis and is degraded. Efficient disposal of defective proteins is essential, because these proteins, even if only partially folded, may compete with their functional counterparts for substrate binding or for complex formation with interaction partners and so exert a dominant negative effect (2). Defective secretory and transmembrane proteins likewise present an inherent risk; if released from the cell or exposed at the cell surface, they could interfere with function.…”