Protein misfolding endoplasmic reticulum

The biosynthetic membrane insertion of eukaryotic membrane proteins almost always takes place cotranslationally, whereas many prokaryotic proteins can be posttranslationally inserted, typically with the aid of chaperones. In eukaryotic cells, the proofreading mechanisms in the endoplasmic reticulum prevent misfolded proteins from leaving to the Golgi. Some of these mechanisms include glycosylation of the protein on... 

Proteasomes are the major cytosolic and nuclear protein degradation machineries and they are also responsible for the proteolysis of misfolded, ER-dislocated (endoplasmic reticulum) proteins [1-3]. Proteasomal protein turnover takes place in an ubiquitin-dependent manner. The proteasome-generated products - ohgopeptides varying in length from 3 to up to 30 amino acid residues - are further processed by aminopeptidases. In higher vertebrates, antigenic peptides are selected from the peptide pool produced by proteasomes and downstream aminopeptidases for presentation on the outer cell surface by major histocompatibility class 1 (MHCl) protein complexes. In this way, proteasomes are essential factors in the detection and eradication of virally infected cells. 

Diabetes can involve misfolding of proteins that form in the endoplasmic reticulum (ER). The ER secretes certain hormones, enzymes, and antibodies, and so is a key player in our health. In some cases, the misfolded proteins interfere with carbohydrate metabolism leading to diabetes. 

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Pilon M, Sdiekman R, Romisch K (1997) Sec61p mediates e]q>ort of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO 116 4540-4548... 

Endoplasmic A highly specific pathway for the degradation of misfolded proteins in the Reticulum- endoplasmic reticulum, which serves as a control mechanism for protein... 

Nakatsukasa K, Brodsky JL. The recognition and retro translocation of misfolded proteins from the endoplasmic reticulum. Traffic. In press. 

Kincaid MM, Cooper AA. Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals. Mol. Biol. Cell 2007 18 455-463. 

The most common CF mutation is a 3-bp deletion that causes the loss of phenylalanine at position 508 (delta 508). This mutation is present in more than 70% of CFTR patients. The defective protein is synthesized in the endoplasmic reticulum, but is misfolded. It is therefore not transported to the Golgi, but is degraded by a proteolytic enzyme complex called the proteosome. Other mutations responsible for CF generate an incomplete mRNA because of premature stop signals, frame shifts, or abnormal splice sites or create a CFTR channel in the membrane that does not function properly. 

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