The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.
In chemistry, a disulfide is a compound containing a R−S−S−R′ functional group or the S2−
2 anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups.
Thioredoxin reductases are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. Both classes are flavoproteins which function as homodimers. Each monomer contains a FAD prosthetic group, a NADPH binding domain, and an active site containing a redox-active disulfide bond.
Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin is linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. Thioredoxins play a role in cell-to-cell communication.
Oxidative protein folding is a process that is responsible for the formation of disulfide bonds between cysteine residues in proteins. The driving force behind this process is a redox reaction, in which electrons pass between several proteins and finally to a terminal electron acceptor.
Tissue transglutaminase is a 78-kDa, calcium-dependent enzyme of the protein-glutamine γ-glutamyltransferases family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis. Aside from its crosslinking function, tTG catalyzes other types of reactions including deamidation, GTP-binding/hydrolyzing, and isopeptidase activities. Unlike other members of the transglutaminase family, tTG can be found both in the intracellular and the extracellular spaces of various types of tissues and is found in many different organs including the heart, the liver, and the small intestine. Intracellular tTG is abundant in the cytosol but smaller amounts can also be found in the nucleus and the mitochondria. Intracellular tTG is thought to play an important role in apoptosis. In the extracellular space, tTG binds to proteins of the extracellular matrix (ECM), binding particularly tightly to fibronectin. Extracellular tTG has been linked to cell adhesion, ECM stabilization, wound healing, receptor signaling, cellular proliferation, and cellular motility.
ER oxidoreductin 1 (Ero1) is an oxidoreductase enzyme that catalyses the formation and isomerization of protein disulfide bonds in the endoplasmic reticulum (ER) of eukaryotes. ER Oxidoreductin 1 (Ero1) is a conserved, luminal, glycoprotein that is tightly associated with the ER membrane, and is essential for the oxidation of protein dithiols. Since disulfide bond formation is an oxidative process, the major pathway of its catalysis has evolved to utilise oxidoreductases, which become reduced during the thiol-disulfide exchange reactions that oxidise the cysteine thiol groups of nascent polypeptides. Ero1 is required for the introduction of oxidising equivalents into the ER and their direct transfer to protein disulfide isomerase (PDI), thereby ensuring the correct folding and assembly of proteins that contain disulfide bonds in their native state.
Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the proteasome.
Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. In humans this oxidation repair enzyme is also known to participate in many cellular functions, including redox signaling and regulation of glucose metabolism. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no oxidoreductase exists that specifically reduces glutaredoxins. Instead, glutaredoxins are reduced by the oxidation of glutathione. Reduced glutathione is then regenerated by glutathione reductase. Together these components compose the glutathione system.
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.
Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme encoded by the autosomal gene PDIA3 in humans. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.
Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a protein that in humans is encoded by the HSPA5 gene.
Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.
Endoplasmic reticulum protein 29 (ERp29) is a chaperone protein that in humans is encoded by the ERP29 gene.
ERO1-like protein alpha is a protein that in humans is encoded by the ERO1L gene.
Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2, also known as GRX2, is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns, spanned 10 kilobase pairs, and localized to chromosome 1q31.2–31.3.
Thioredoxin domain-containing protein 5 is a protein that in humans is encoded by the TXNDC5 gene.
DsbA is a bacterial thiol disulfide oxidoreductase (TDOR). DsbA is a key component of the Dsb family of enzymes. DsbA catalyzes intrachain disulfide bond formation as peptides emerge into the cell's periplasm.
Thioredoxins are small disulfide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulfide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of 2 cysteine thiol groups to a disulfide, accompanied by the transfer of 2 electrons and 2 protons. The net result is the covalent interconversion of a disulfide and a dithiol.
Protein disulfide isomerase family A member 2 is a protein that in humans is encoded by the PDIA2 gene.
