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At least 721 records · Page 40Linked to original sources
PubMed1992

Proteolytic cleavages of proalbumin and complement Pro-C3 in vitro by a truncated soluble form of furin, a mammalian homologue of the yeast Kex2 protease.

We have recently purified and characterized a truncated soluble form of furin from which the predicted transmembrane domain and cytoplasmic tail were deleted (Hatsuzawa, K., Nagahama, M., Takahashi, S., Takada, K., Murakami, K., and Nakayama, K. (1992) J. Biol. Chem. 267, 16094-16099). Our results showed that furin resembles the yeast Kex2 protease with respect to both its enzymic properties and substrate specificity. Here we demonstrate that the soluble form of furin is capable of converting the precursors of albumin and the third component of complement (proalbumin and pro-C3, respectively) in vitro to mature proteins. Thus furin mimics the Ca(2+)-dependent proalbumin and pro-C3 convertases found in the Golgi membranes (Brennan, S. O., and Peach, R. J. (1988) FEBS Lett. 229, 167-170; Oda, K. (1992) J. Biol. Chem. 267, 17465-17471). Furthermore we show that the variant alpha 1-antitrypsin Pittsburgh, which is a specific inhibitor of the Golgi proalbumin convertase, inhibits not only the Golgi pro-C3 convertase, but also the soluble furin. These results suggest a role for furin in the cleavage of proproteins transported via the constitutive pathway.

Animals↗
PubMed1998

Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: potential role of other convertases in mammalian cells.

Sequence analysis of the adhesion molecule E-cadherin had revealed a multibasic motif [4PArg-Gln-Lys-Arg1P], reminiscent of the minimal cleavage signal for furin, the prototype of the proprotein convertase family, and/or other members sharing similar sequence specificity. Mutation of this site was sufficient to abolish processing of E-cadherin in fibroblasts reinforcing the possibility that proprotein convertases are involved in the maturation of this adhesion molecule. Here we demonstrate that even though furin can efficiently and specifically cleave proE-cadherin in a baculovirus-based co-expression system, the furin-deficient LoVo cells were found to process endogenous E-cadherin as efficiently as normal cell lines. This suggests, for the first time, that E-cadherin is not only a substrate for furin but for other mammalian convertases sharing similar sequence specificity.

Amino Acid Sequence↗
PubMed2000

Involvement of the membrane lipid bilayer in sorting prohormone convertase 2 into the regulated secretory pathway.

Prohormone convertase 2 (PC2) is a neuroendocrine-specific protease involved in the intracellular maturation of prohormones and proneuropeptides. PC2 is synthesised as a proprotein (proPC2) that undergoes proteolysis, aggregation and membrane association during its transit through the regulated secretory pathway. We have previously shown that the pro region of proPC2 plays a key role in its aggregation and membrane association. To investigate this further, we determined the binding properties of a peptide containing amino acids 45-84 of proPC2 (proPC2(45-84)) to trans-Golgi network/granule-enriched membranes from the AtT20 cell line. Removal of peripheral membrane proteins or hydrolysis of integral membrane proteins did not affect the binding properties of proPC2(45-84). Rather, proPC2(45-84) was shown to bind to protein-free liposomes in a pH- and Ca(2+)-dependent manner. To identify the component of the lipid bilayer involved in this membrane association, we used chromaffin-granule membranes and studied the binding properties of the endogenous PC2. Treatment of the membranes with saponin, a cholesterol-depleting detergent, failed to extract PC2 from the membranes, whereas chromogranin A (CgA) was removed. Treatment of the membranes with Triton X-100 yielded a low-density detergent-insoluble fraction enriched in PC2, but not CgA. The detergent-insoluble fraction also contained glycoprotein III, known to be part of the lipid rafts (membrane microdomains rich in sphingolipids). Finally, sphingolipid depletion of AtT20 cells resulted in the mis-sorting of PC2, suggestive of a link between the association of PC2 with lipid rafts in the membrane and its sorting into the regulated secretory pathway.

Animals↗
PubMed1996

Isolation of the human PC6 gene encoding the putative host protease for HIV-1 gp160 processing in CD4+ T lymphocytes.

Production of infectious HIV-1 virions is dependent on the processing of envelope glycoprotein gp160 by a host cell protease. The protease in human CD4+ T lymphocytes has not been unequivocally identified, yet members of the family of mammalian subtilisin-like protein convertases (SPCs), which are soluble or membrane-bound proteases of the secretory pathway, best fulfill the criteria. These proteases are required for proprotein maturation and cleave at paired basic amino acid motifs in numerous cellular and viral glycoprotein precursors, both in vivo and in vitro. To identify the gp160 processing protease, we have used reverse transcription-PCR and Northern blot analyses to ascertain the spectrum of SPC proteases in human CD4+ T cells. We have cloned novel members of the SPC family, known as the human PC6 genes. Two isoforms of the hPC6 protease are expressed in human T cells, hPC6A and the larger hPC6B. The patterns of SPC gene expression in human T cells has been compared with the furin-defective LoVo cell line, both of which are competent in the production of infectious HIV virions. This comparison led to the conclusion that the hPC6 gene products are the most likely candidates for the host cell protease responsible for HIV-1 gp160 processing in human CD4+ T cells.

Amino Acid Sequence↗
PubMed2001

Association of prohormone convertase 3 with membrane lipid rafts.

Prohormone convertase 3 (PC3) is a neuroendocrine-specific member of the subtilisin-kexin family, involved in the intracellular processing and maturation of prohormones and proneuropeptides. PC3 is synthesised as a proprotein that undergoes two different cleavages resulting in the mature PC3 and the enzymatically active PC3DeltaC. In vitro translated proPC3 and proPC3DeltaC bind to trans-Golgi network (TGN)/granule-enriched membranes from the AtT20 neuroendocrine cell line in a pH-dependent manner suggesting both a dominant role for the pro-region in membrane association and that the C-terminal region is not essential. However, while PC3 bound to membranes the majority of PC3DeltaC did not, suggesting that either the pro-region or the C-terminal region of PC3 is required for membrane association. Removal of peripheral membrane proteins did not affect the binding properties of any of the in vitro translated proteins. Chromaffin granule membranes (CGMs) were used to study the binding characteristics of endogenous PC3 and its active C-terminal truncated counterpart (PC3DeltaC). Incubation of CGMs with Triton X-100 did not completely solubilise either of these forms of PC3. Moreover, both PC3 and PC3DeltaC remained associated with detergent-resistant membrane microdomains, termed lipid rafts, purified from CGMs. The data raise the possibility that PC3 and PC3DeltaC are sorted to the regulated secretory pathway via their association with membrane lipid rafts.

Aspartic Acid Endopeptidases↗
PubMed2004

The kindest cuts of all: crystal structures of Kex2 and furin reveal secrets of precursor processing.

Pro-hormone or pro-protein convertases are a conserved family of eukaryotic serine proteases found in the secretory pathway. These endoproteases mature precursors for peptides and proteins that perform a wide range of physiologically important and clinically relevant functions. The first member of this family to be identified was Kex2 in the yeast Saccharomyces cerevisiae. One mammalian member of this family - furin - is responsible for processing substrates that include insulin pro-receptor, human immunodeficiency virus gp160 glycoprotein, Ebola virus glycoprotein, and anthrax protective antigen. Recent determination of the crystal structures for the catalytic core domains of both Kex2 and furin - the first for any members of this family - provide remarkable insights and a new level of understanding of substrate specificity and catalysis by the pro-protein convertases.

Animals↗
PubMed2004

Role of subtilisin-like convertases in cadherin processing or the conundrum to stall cadherin function by convertase inhibitors in cancer therapy.

Cadherins are a family of intercellular adhesion receptors. Produced as inactive precursors, they become functional adhesion molecules after proteolytic cleavage by subtilisin-like pro-protein convertases (PCs). Owing to their activation and assembly into multiprotein adhesion complexes at sites of cell contacts, adhesion-competent cadherins are prerequisite for tissue integrity. In recent years evidence has accumulated that intercellular junctions not only provide mechanical linkage, but in addition are potent modulators of signalling cascades. This infers a biological role to intercellular adhesion complexes that is significantly more complex and powerful. Currently, the broad implications of disturbances in somatic tissue adhesion components are only just beginning to emerge. Prominent examples of adhesion defects include autoimmune diseases, or tumour invasion and metastasis and malignant transformation. This review reports on our current knowledge of cadherin function and their maturation by pro-protein convertases, and puts special emphasis on the consequences of pro-protein convertase inhibition for epithelial tissue homeostasis.

Animals↗
PubMed1998

CaaX converting enzymes.

Proteins that contain a carboxyl-terminal CaaX motif undergo post-translational processing involving prenylation, endoproteolysis and methylesterification. Two yeast genes, AFC1 and RCE1, which are candidates for genes encoding CaaX converting enzymes, were recently identified. Rce1p is required for the full penetrance of the activated Ras2pval19 phenotype in yeast, indicating its possible utility as a new target in Ras-based malignancies. Advances in our current understanding of CaaX convertases and the functional importance of CaaX proteolysis are discussed.

Amino Acid Sequence↗
PubMed1997

Expression of PC3, carboxypeptidase E and enkephalin in human monocyte-derived macrophages as a tool for genetic studies.

Circulating monocytes in human peripheral blood are readily available, easily obtained, and can be cultured in vitro. Once plated, the monocytes spontaneously differentiate into macrophages. Undifferentiated human monocytes do not express carboxypeptidase E (CPE), prohormone convertase 3 (PC3/PC1) or proenkephalin (ENK), suggesting that gene induction during differentiation results in the expression of these genes. RT-PCR of human monocyte-derived macrophage (HMDM) mRNA showed detectable levels of ENK mRNA at 48 h after plating, followed by PC3 and CPE mRNAs at 72 h. PC3 expression was confirmed by Western blotting in THP-1 cells. Similarities in expression of enzymes involved in the conversion of neuroendocrine precursors, such as proenkephalin, into functionally mature peptides underscores the close association HMDMs may share with the neuroendocrine system. Because of this, HMDMs may prove to be a valuable, non-surgical source of human tissue for clinical genetic diagnosis of some convertase disorders.

Aspartic Acid Endopeptidases↗
PubMed2000

Expression and localization of prohormone convertase 1/3 (SPC3) in porcine ovary.

Tissue distribution and cellular localization of PC1/3 mRNA in porcine tissues were examined by ribonuclease protection assay and in situ hybridization. PC1/3 mRNA was detected mainly in the corpus luteum of pregnant sow and brain. Within the ovary, PC1/3 and relaxin transcripts colocalized within large luteal cells. Levels of PC1/3 transcripts in corpora lutea increased as gestation advanced, parallel with an observed increase in relaxin transcripts. A role for PC1/3 in proprotein processing in the ovary is discussed.

Animals↗
PubMed2003

Molecular characterization of the cDNA and localization of the mRNA encoding the prohormone convertase PC5-A in the European green frog.

The structure and distribution of PC5-A, a prohormone convertase that is thought to be involved in post-translational processing of peptide hormone and neuropeptide precursors, have not been investigated in submammalian vertebrates. In the present study, we characterized the cDNA encoding PC5-A in the European green frog Rana esculenta. The frog PC5-A cDNA encodes a 913-amino acid protein that encompasses a 28-amino acid signal peptide, the Asp/His/Ser catalytic triad found in all serine proteinases of the subtilisin family, and two potential N-linked glycosylation sites located in a C-terminal cysteine-rich domain. Reverse transcriptase polymerase chain reaction amplification showed that PC5-A mRNA is expressed in various organs including the brain, spinal cord, pituitary, lung, liver, intestine, and testis, but not in the stomach and pancreas. The distribution of PC5-A mRNA in the frog brain was studied by in situ hybridization histochemistry. Intense expression was observed in the mitral cellular layer of the olfactory bulb, the nucleus of the diagonal band of Broca, the anterior preoptic area, and the suprachiasmatic and ventral hypothalamic nuclei. The expression pattern of PC5-A mRNA in the central nervous system of anuran amphibians was consistent with the implication of this prohormone convertase in the processing of various neuropeptide precursors.

Amino Acid Sequence↗