Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary spherocytosis (HS) is a common inherited hemolytic anemia caused by mutations in erythrocyte proteins including the anion exchanger, AE1 (band 3). This study examined seven missense mutations (L707P, R760Q, R760W, R808C, H834P, T837M, and R870W) located in the membrane domain of the human AE1 that are associated with this disease. The HS mutants, constructed in full-length AE1 cDNA, could be transiently expressed to similar levels in HEK 293 cells. Immunofluorescence, cell surface biotinylation, and pulse chase labeling showed that the HS mutants all exhibited defective cellular trafficking from the endoplasmic reticulum to the plasma membrane. Impaired binding to an inhibitor affinity matrix indicated that the mutant proteins had non-native structures and may be misfolded. Further characterization of the HS R760Q mutant showed no change in its oligomeric structure or turnover (half-life = 15 h) compared to wild-type AE1, suggesting the mutant was not aggregated or targeted for rapid degradation via the proteasome. Intracellular retention of HS mutant AE1 would lead to destruction of the protein during erythroid development and would account for the lack of HS mutant AE1 in the plasma membrane of the mature red cell.
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PMID:Trafficking and folding defects in hereditary spherocytosis mutants of the human red cell anion exchanger. 1120 88

Various mutations in the AE1 (anion exchanger 1, band 3) gene cause dominant hereditary spherocytosis, a common congenital hemolytic anemia associated with deficiencies of AE1 of different degrees and loss of mutant protein from red blood cell membranes. To determine the mechanisms underlying decreases in AE1 protein levels, we employed K562 and HEK293 cell lines and Xenopus oocytes together with bovine wild-type AE1 and an R664X nonsense mutant responsible for dominant hereditary spherocytosis to analyze protein expression, turnover, and intracellular localization. R664X-mutant protein underwent rapid degradation and caused specifically increased turnover and impaired trafficking to the plasma membrane of the wild-type protein through hetero-oligomer formation in K562 cells. Consistent with those observations, co-expression of mutant and wild-type AE1 reduced anion transport by the wild-type protein in oocytes. Transfection studies in K562 and HEK293 cells revealed that the major pathway mediating degradation of both R664X and wild-type AE1 employed endoplasmic reticulum (ER)-associated degradation through the proteasomal pathway. Proteasomal degradation of R664X protein appeared to be independent of both ubiquitylation and N-glycosylation, and aggresome formation was not observed following proteasome inhibition. These findings indicate that AE1 R664X protein, which is associated with dominant hereditary spherocytosis, has a dominant-negative effect on the expression of wild-type AE1.
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PMID:Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle. 1691 75

An R664X nonsense mutant AE1 is responsible for dominant hereditary spherocytosis in cattle and is degraded by the proteasomal endoplasmic reticulum-associated degradation. The present study demonstrated that R664X AE1 translated in vitro had the trypsin-sensitve site identical to that of the wild-type AE1. The P661S/R664X mutant containing a possible N-glycosylation site at Asn660 showed an increase in size by 3 kDa both in the cell-free translation system and in transfected HEK293 cells. Moreover, steady state levels of R664X and P661S/R664X in HEK293 cells were markedly increased in the presence of a proteasome inhibitior. These findings indicate that the truncated C-terminal region of R664X AE1 has lumenal localization in the endoplasmic reticulum and is not accessible to proteasomal machineries in the cytosol.
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PMID:Lumenal localization in the endoplasmic reticulum of the C-terminal tail of an AE1 mutant responsible for hereditary spherocytosis in cattle. 1740 56

The structure and function of the red cell anion exchanger 1 (AE1, Band 3, SLC4A1), the truncated kidney anion exchanger 1 (kAE1), and the other members of the SLC4 family of bicarbonate transporters are reviewed. Mutations in the AE1 gene cause human diseases like Southeast Asian ovalocytosis and hereditary spherocytosis in the red cell and distal renal tubular acidosis in the kidney. These mutations affect the folding, trafficking, and functional expression of these membrane glycoproteins. In the SLC26 family of anion transporters, mutations also cause trafficking defects and human disease. Membrane glycoproteins are cotranslationally N-glycosylated in the endoplasmic reticulum (ER) and when properly folded, traffic via the secretory pathway to their final destination such as the plasma membrane. Misfolded glycoproteins are retained in ER and are targeted for degradation by the proteasome following retrotranslocation and ubiquitinylation. ER chaperones, like membrane-bound calnexin, interact transiently with glycoproteins and are part of the quality control system that monitors the folding of glycoproteins during their biosynthesis. Recent results have indicated that it is possible to "correct" trafficking defects caused by some mutations in the SLC4 and 26 families through the use of small molecules that interfere with the interaction of glycoproteins with the components of the quality control system. This review summarizes the current knowledge on structure and function of anion transporters from the SLC4 and SLC26 families, and the effect of mutations on their trafficking and functional expression.
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PMID:Structure, function, and trafficking of SLC4 and SLC26 anion transporters. 2474 80