Abstract
The endoplasmic reticulum (ER) is site of synthesis and maturation of membrane and secretory proteins in eukaryotic cells. The ER contains more than 20 members of the Protein Disulfide Isomerase (PDI) family. These enzymes regulate formation, isomerization and disassembly of covalent bonds between cysteine residues. As such, PDIs ensure protein folding, which is required to attain functional and transport-competent structure, and protein unfolding, which facilitates dislocation of defective gene products across the ER membrane for ER-associated degradation (ERAD). The PDI family includes over a dozen of soluble members and few membrane-bound ones. Among these latter, there are five PDIs grouped in the thioredoxin-related transmembrane (TMX) protein family. In this review, we summarize the current knowledge on TMX1, TMX2, TMX3, TMX4 and TMX5, their structural features, regulation and roles in biogenesis and control of the mammalian cell’s proteome.
Highlights
About one third of the proteome in eukaryotic cells is made of membrane and secretory proteins [1].Their production and maturation occurs within the endoplasmic reticulum (ER) with help and under surveillance of resident chaperones and folding enzymes, such as the members of the Protein Disulfide Isomerase (PDI) family [2]
PDIs assist protein folding by catalyzing the formation of the native set of intra- and inter-molecular disulfide bonds; they can correct structural errors by disassembling non-native disulfides to promote their conversion into the native set [3,4]; they can facilitate the translocation across the ER membrane of terminally misfolded polypeptides by dissolving intra- and inter-molecular disulfide bonds, in a step that precedes their degradation by cytosolic 26S-proteasomes [5,6]
Among the more than 20 members of the PDI family, TMX1 represents the first example of topology-specific redox catalyst involved in both protein folding and ER-associated degradation (ERAD) pathways
Summary
About one third of the proteome in eukaryotic cells is made of membrane and secretory proteins [1]. PDIs assist protein folding by catalyzing the formation of the native set of intra- and inter-molecular disulfide bonds (oxidation); they can correct structural errors by disassembling non-native disulfides to promote their conversion into the native set (isomerization) [3,4]; they can facilitate the translocation across the ER membrane of terminally misfolded polypeptides by dissolving intra- and inter-molecular disulfide bonds (reduction), in a step that precedes their degradation by cytosolic 26S-proteasomes [5,6]. Deletion of the TMX1 gene is innocuous at the cellular level This suggests the activation of compensatory mechanisms in cultured where other members of the PDI family may play a role [26].
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