Basic Amino Acid Conjugates of 1,2‐Diselenan‐4‐amine with Protein Disulfide Isomerase‐like Functions as a Manipulator of Protein Quality Control

2020 ◽  
Vol 15 (17) ◽  
pp. 2646-2652 ◽  
Author(s):  
Shunsuke Tsukagoshi ◽  
Rumi Mikami ◽  
Kenta Arai
Keyword(s):  
Quality Control ◽  
Amino Acid ◽  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Basic Amino Acid ◽  
Disulfide Isomerase ◽  
Amino Acid Conjugates ◽  
Protein Disulfide

scholarly journals Abnormal Enhancement of Protein Disulfide Isomerase-like Activity of a Cyclic Diselenide Conjugated with a Basic Amino Acid by Inserting a Glycine Spacer

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1090
Author(s):  
Rumi Mikami ◽  
Shunsuke Tsukagoshi ◽  
Kenta Arai
Keyword(s):  
Catalytic Activity ◽  
Amino Acid ◽  
Protein Disulfide Isomerase ◽  
Basic Amino Acid ◽  
Amide Bond ◽  
Disulfide Isomerase ◽  
Protein Substrates ◽  
Oxidative Protein Folding ◽  
Catalytic Mechanisms ◽  
Protein Disulfide

In a previous study, we reported that (S)-1,2-diselenane-4-amine (1) catalyzes oxidative protein folding through protein disulfide isomerase (PDI)-like catalytic mechanisms and that the direct conjugation of a basic amino acid (Xaa: His, Lys, or Arg) via an amide bond improves the catalytic activity of 1 by increasing its diselenide (Se–Se) reduction potential (E′°). In this study, to modulate the Se–Se redox properties and the association of the compounds with a protein substrate, new catalysts, in which a Gly spacer was inserted between 1 and Xaa, were synthesized. Exhaustive comparison of the PDI-like catalytic activities and E′° values among 1, 1-Xaa, and 1-Gly-Xaa showed that the insertion of a Gly spacer into 1-Xaa either did not change or slightly reduced the PDI-like activity and the E′° values. Importantly, however, only 1-Gly-Arg deviated from this generality and showed obviously increased E°′ value and PDI-like activity compared to the corresponding compound with no Gly spacer (1-Arg); on the contrary, its catalytic activity was the highest among the diselenide compounds employed in this study, while this abnormal enhancement of the catalytic activity of 1-Gly-Arg could not be fully explained by the thermodynamics of the Se–Se bond and its association ability with protein substrates.

scholarly journals The anterior gradient-2 interactome

2020 ◽  
Vol 318 (1) ◽  
pp. C40-C47 ◽  
Author(s):  
Frederic Delom ◽  
M. Aiman Mohtar ◽  
Ted Hupp ◽  
Delphine Fessart
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Physiological Role ◽  
Disulfide Isomerase ◽  
Cellular Effects ◽  
Binding Partners ◽  
Protein Disulfide ◽  
Biological Outcomes

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum

2009 ◽  
Vol 417 (3) ◽  
pp. 651-666 ◽  
Author(s):  
Marek Michalak ◽  
Jody Groenendyk ◽  
Eva Szabo ◽  
Leslie I. Gold ◽  
Michal Opas
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Embryonic Development ◽  
Protein Disulfide Isomerase ◽  
Biological Systems ◽  
Disulfide Isomerase ◽  
Calcium Buffering ◽  
Process Property ◽  
Protein Disulfide ◽  
Er Membrane

Calreticulin is an ER (endoplasmic reticulum) luminal Ca2+-buffering chaperone. The protein is involved in regulation of intracellular Ca2+ homoeostasis and ER Ca2+ capacity. The protein impacts on store-operated Ca2+ influx and influences Ca2+-dependent transcriptional pathways during embryonic development. Calreticulin is also involved in the folding of newly synthesized proteins and glycoproteins and, together with calnexin (an integral ER membrane chaperone similar to calreticulin) and ERp57 [ER protein of 57 kDa; a PDI (protein disulfide-isomerase)-like ER-resident protein], constitutes the ‘calreticulin/calnexin cycle’ that is responsible for folding and quality control of newly synthesized glycoproteins. In recent years, calreticulin has been implicated to play a role in many biological systems, including functions inside and outside the ER, indicating that the protein is a multi-process molecule. Regulation of Ca2+ homoeostasis and ER Ca2+ buffering by calreticulin might be the key to explain its multi-process property.

scholarly journals Protein disulfide isomerase ERp57 protects early muscle denervation in experimental ALS

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Pablo Rozas ◽  
Cristina Pinto ◽  
Francisca Martínez Traub ◽  
Rodrigo Díaz ◽  
Viviana Pérez ◽  
...  
Keyword(s):  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Neuromuscular Junctions ◽  
Point Mutations ◽  
Central Component ◽  
Control Mechanisms ◽  
Neuroprotective Effects ◽  
Disulfide Isomerase ◽  
Mutant Sod1 ◽  
Protein Disulfide

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that affects motoneurons. Mutations in superoxide dismutase 1 (SOD1) have been described as a causative genetic factor for ALS. Mice overexpressing ALS-linked mutant SOD1 develop ALS symptoms accompanied by histopathological alterations and protein aggregation. The protein disulfide isomerase family member ERp57 is one of the main up-regulated proteins in tissue of ALS patients and mutant SOD1 mice, whereas point mutations in ERp57 were described as possible risk factors to develop the disease. ERp57 catalyzes disulfide bond formation and isomerization in the endoplasmic reticulum (ER), constituting a central component of protein quality control mechanisms. However, the actual contribution of ERp57 to ALS pathogenesis remained to be defined. Here, we studied the consequences of overexpressing ERp57 in experimental ALS using mutant SOD1 mice. Double transgenic SOD1G93A/ERp57WT animals presented delayed deterioration of electrophysiological activity and maintained muscle innervation compared to single transgenic SOD1G93A littermates at early-symptomatic stage, along with improved motor performance without affecting survival. The overexpression of ERp57 reduced mutant SOD1 aggregation, but only at disease end-stage, dissociating its role as an anti-aggregation factor from the protection of neuromuscular junctions. Instead, proteomic analysis revealed that the neuroprotective effects of ERp57 overexpression correlated with increased levels of synaptic and actin cytoskeleton proteins in the spinal cord. Taken together, our results suggest that ERp57 operates as a disease modifier at early stages by maintaining motoneuron connectivity.

scholarly journals Export of a Cysteine-Free Misfolded Secretory Protein from the Endoplasmic Reticulum for Degradation Requires Interaction with Protein Disulfide Isomerase

1999 ◽  
Vol 147 (7) ◽  
pp. 1443-1456 ◽  
Author(s):  
Pauline Gillece ◽  
José Manuel Luz ◽  
William J. Lennarz ◽  
Francisco Javier de la Cruz ◽  
Karin Römisch
Keyword(s):  
Quality Control ◽  
Protein Disulfide Isomerase ◽  
Secretory Protein ◽  
Secretory Proteins ◽  
Disulfide Isomerase ◽  
Thiol Content ◽  
Mutant Forms ◽  
Protein Disulfide ◽  
Chemical Cross Linking ◽  
Er Membrane

Protein disulfide isomerase (PDI) interacts with secretory proteins, irrespective of their thiol content, late during translocation into the ER; thus, PDI may be part of the quality control machinery in the ER. We used yeast pdi1 mutants with deletions in the putative peptide binding region of the molecule to investigate its role in the recognition of misfolded secretory proteins in the ER and their export to the cytosol for degradation. Our pdi1 deletion mutants are deficient in the export of a misfolded cysteine-free secretory protein across the ER membrane to the cytosol for degradation, but ER-to-Golgi complex transport of properly folded secretory proteins is only marginally affected. We demonstrate by chemical cross-linking that PDI specifically interacts with the misfolded secretory protein and that mutant forms of PDI have a lower affinity for this protein. In the ER of the pdi1 mutants, a higher proportion of the misfolded secretory protein remains associated with BiP, and in export-deficient sec61 mutants, the misfolded secretory protein remain bounds to PDI. We conclude that the chaperone PDI is part of the quality control machinery in the ER that recognizes terminally misfolded secretory proteins and targets them to the export channel in the ER membrane.

Sign in / Sign up

Export Citation Format

Share Document