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Intracellular polym...
Intracellular polymerization of the serpin plasminogen activator inhibitor type 2.
- Artikel/kapitelEngelska1996
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LIBRIS-ID:oai:DiVA.org:umu-59918
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-59918URI
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Språk:engelska
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Sammanfattning på:engelska
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Plasminogen activator inhibitor type 2 (PAI-2) is synthesized in two molecular forms: an intracellular, nonglycosylated form and an extracellular, glycosylated form. The bitopological distribution of PAI-2 is caused by an inefficient internal secretion signal. In addition, the secretion efficiency of PAI-2 seems to differ, depending on the cell type, differentiation state, and culture conditions. In recombinant cell clones designed for the synthesis of the secreted form of PAI-2, the fraction of secreted PAI-2 decreased with increasing expression levels. Subcellular fractionation of cell clones with higher expression levels revealed that PAI-2 accumulating in the cell was mainly associated with the organelles of the secretory pathway. Electrophoresis under nondenaturating conditions revealed that the PAI-2 retained at higher expression levels was mainly polymerized. Polymers of PAI-2 were also detected in cytosolic extracts prepared from human placenta and phorbol ester-stimulated U 937 cells, indicating that intracellular polymerization of PAI-2 may occur in the cytosols of cells that normally express PAI-2 under physiological conditions. When purified PAI-2 or cellular extracts were incubated at 37 degrees C for 24 h most of the PAI-2 protein was found to polymerize. Polymer formation was prevented by the addition of synthetic peptides with sequences corresponding to residues P2 to P14 in the reactive center loop of PAI-2 and antithrombin. These synthetic peptides also caused dissociation of prepolymerized purified PAI-2 and PAI-2 polymers in cellular extracts. Incubation with unrelated peptides of the same size had no effect on polymer formation or dissociation of preformed polymers, indicating that polymerization of PAI-2 occurs by the loop-sheet mechanism. Taken together, our data suggest that the wild-type form of PAI-2, like some natural pathological genetic variants of alpha1-antitrypsin, antithrombin, and C1 inhibitor readily polymerizes intracellularly and that polymerization may lead to a reduced secretion efficiency.
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Ny, TorUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)tony0001
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Umeå universitetInstitutionen för medicinsk kemi och biofysik
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Ingår i:Journal of Biological Chemistry271:17, s. 10048-530021-92581083-351X
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