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PubMed1992

Signal peptidases in prokaryotes and eukaryotes--a new protease family.

Signal peptidases remove targeting peptides from pre-proteins and play central roles in the secretory pathway, as well as in the delivery of proteins to the mitochondrial intermembrane space and to the lumen of thylakoids. The catalytic mechanism of pre-protein cleavage has long been an enigma, but recent data from site-directed mutagenesis and sequence alignment studies suggest that signal peptidases may constitute a new type of serine protease, mechanistically related to the beta-lactamases.

Amino Acid Sequence↗
PubMed2004

Sequence and evolutionary analysis of the human trypsin subfamily of serine peptidases.

Serine peptidases (SP) are peptidases with a uniquely activated serine residue in the substrate-binding site. SP can be classified into clans with distinct evolutionary histories and each clan further subdivided into families. We analyzed 79 proteins representing the S1A subfamily of human SP, obtained from different databases. Multiple alignment identified 87 highly conserved amino acid residues. In most cases of substitution, a residue of similar character was inserted, implying that the overall character of the local region was conserved. We also identified several conserved protein motifs. 7-13 cysteine positions, potentially forming disulfide bridges, were also found to be conserved. Most members are secreted as inactive (pro) forms with a trypsin-like cleavage site for activation. Substrate specificity was predicted to be trypsin-like for most members, with few chymotrypsin-like proteins. Phylogenetic analysis enabled us to classify members of the S1A subfamily into structurally related groups; this might also help to functionally sort members of this subfamily and give an idea about their possible functions.

Amino Acid Motifs↗
PubMed2005

Involvement of placental peptidases associated with renin-angiotensin systems in preeclampsia.

Preeclampsia is characterized by pregnancy-induced hypertension accompanied with protein urea and generalized edema. Preeclampsia develops during the second half of pregnancy and resolves postpartum promptly, implicating the placenta as a primary cause in the disorder. Normal pregnancy is associated with reductions in arterial pressure and attenuated pressor response to exogenous infused angiotensin II (ANG II). In contrast, women with preeclampsia show the similar sensitivity to the pressor effect of ANG II as do non-pregnant women. To elucidate the involvement of placental peptidases associated with renin-angiotensin systems, we determined the localization of angiotensin-converting enzyme (ACE) and aminopeptidase A (AP-A), ANG II degrading enzyme, in the placenta and compared the expression of mRNA and protein in uncomplicated and preeclamptic placenta. In addition, AP-A expression in trophoblastic cells treated with ANG II and ACE expression in HUVECs under hypoxic condition were analyzed, respectively. The expression of both peptidases in the preeclamptic placenta was significantly higher than those from uncomplicated. ACE was primarily localized to venous endothelial cells of stem villous whereas AP-A expression was recognized in the trophoblast and pericytes of fetal arterioles and venules within stem villous. Hypoxia induced ACE expression in HUVECs while both hypoxia and ANG II evoked AP-A expression in trophoblast. These results suggested that hypoxic condition in preeclampsia induces ACE activation in feto-placental unit to maintain the fetal hemodynamics and placental AP-A plays a role as a component of the barrier of ANG II between mother and fetus.

Angiotensin I↗
PubMed2006

Characterization and role of Peptidase N from Salmonella enterica serovar Typhimurium.

ATP-independent peptidases are important during the distal steps of cytosolic protein degradation. The contribution of a member of this group, Peptidase N (PepN) was studied in Salmonella enterica serovar Typhimurium (Salmonella typhimurium). The DeltapepN strain displays greatly reduced cleavage of 9 out of a total of 13 exopeptidase substrates, demonstrating a significant contribution of PepN to cytosolic aminopeptidase activity. The cleavage profile of purified S. typhimurium PepN is Arg>Ala>Thr, demonstrating broad specificity. Comparative biochemical studies with purified PepN from Escherichia coli and S. typhimurium revealed the latter to be distinct: S. typhimurium PepN cleaves Thr-AMC more efficiently and is less sensitive to inhibition by N-ethylmaleimide. Studies with DeltapepN and PepN overexpression demonstrated its importance for growth during nutritional downshift in combination with high temperature stress. In summary, S. typhimurium PepN contributes significantly to cytosolic aminopeptidase activity and its role is manifested under selected stress conditions.

Aminopeptidases↗
PubMed2006

Insights into the substrate specificity of a novel snake venom serine peptidase by molecular modeling.

The cDNA encoding BthaTL, a serine peptidase from the venom of the snake Bothrops alternatus, was cloned and sequenced. The deduced primary structure shows over 62% of identity with snake venom thrombin-like enzymes (SVTLEs), molecules with high substrate specificity toward different natural substrates. Indeed, a phylogenetic reconstruction by two different methods clustered this enzyme close to other SVTLEs. These enzymes generally affect the hemostatic system in several ways, and therefore are used as tools in pharmacology and clinical diagnosis. A three-dimensional model of BthaTL was built by homology modeling using TSV-PA (Trimeresurus stejnegeri venom plasminogen activator) crystal structure as template. BthaTL model showed that the typical catalytic triad conformation of serine peptidases was preserved. The calcium coordination ligands were absent or adopt an unfavorable conformation, preventing interactions with metals. On the other hand, the Asp97-Arg174 saline bridge of TSV-PA was not found and its specificity determinant Phe193 is replaced by a Gly in BthaTL. The substitution of essential residues in the neighborhoods of the catalytic site cleft of BthaTL indicates that these two proteins do not share the same enzymatic specificity, what means that BthaTL will probably not activate plasminogen. Such observations may be helpful in the understanding of the molecular mechanism for substrate specificity of these enzymes.

Amino Acid Sequence↗
PubMed2006

Molecular characterization and classification of a clip domain containing peptidase from the ectoparasite Lepeophtheirus salmonis (Copepoda, Crustacea).

Clip domain containing serine peptidases (CSPs) include one or more N-terminal clip domain(s) and a C-terminal serine peptidase domain that shares traits with both chymotrypsin and trypsin. CSPs are found in arthropods and are involved in embryonic patterning, immune responses and blood clotting. Among crustaceans only one CSP, which activates prophenoloxidase in crayfish, have previously been reported. We here present LsCSP1, the first CSP found in copepods. LsCSP1 is expressed in the subcuticular tissue and the transcription appears to be upregulated during development. In conjunction with previous studies of CSPs, this study suggests that LsCSP1 may play a role in the immune responses of L. salmonis. Phylogenetic and structural analyses indicate that the CSPs and catalytically inactive CSP homologs (CSPHs) constitute a monophyletic lineage.

Amino Acid Sequence↗
PubMed2004

Proteasome and peptidase function in MHC-class-I-mediated antigen presentation.

MHC-class-I-presented peptides are predominantly generated by the proteasome system. IFN-gamma strongly influences the processing efficiency by inducing immunoproteasome formation and proteasome activator PA28 synthesis. Depending on the protein substrate, the presence of immunoproteasomes and PA28 influence epitope liberation either positively or negatively. Abundantly occurring defective ribosomal products are a major source for proteasome-dependent antigen processing; however, antigen presentation is relatively inefficient. This is in part due to the existence of a panel of cytosolic aminopeptidases, such as bleomycin hydrolase (BH), puromycin-sensitive aminopeptidase (PSA) and thimet oligoendopeptidase (TOP), that can destroy epitopes or their precursors. Other aminopeptidases, such as leucine aminopeptidase (LAP) and endoplasmic reticulum aminopeptidase 1 (ERAP 1), can trim epitope precursors from the amino terminus to their correct size for MHC class I binding to enhance antigen presentation. Recent evidence suggests that tripeptidyl peptidase II (TPPII), a large peptidase with exo-and endo-proteolytic activities, is also involved in antigen processing and may generate a specific set of MHC class I epitopes.

Aminopeptidases↗
PubMed2004

His507 of acylaminoacyl peptidase stabilizes the active site conformation, not the catalytic intermediate.

Acylaminoacyl peptidase is a member of the prolyl oligopeptidase family. Amino acid sequence alignment suggests that the stabilization of the tetrahedral intermediate should be mediated by His507 rather than by a tyrosine residue found in the other family members of this serine peptidase group. The pH dependence of k(cat)/K(m) did not reveal any effect of His507. Substitution of an alanine for His507 gave the same bell-shaped pH rate profile with the same pK(a) values (7.0 and 8.7). However, the value of the rate constant was 85 times lower with the modified enzyme, which indicated that His507 is an important residue that is probably involved in the formation of the 3-dimensional structure.

Amino Acid Sequence↗
PubMed2005

Biolistic transformation of Schistosoma mansoni with 5' flanking regions of two peptidase genes promotes tissue-specific expression.

The gene-regulatory elements controlling peptidase expression in Schistosoma mansoni are unknown. A genomic DNA library was constructed from which 5' flanking fragments of the cathepsins F (SmCF; 649 bp) and B2 (SmCB2; 810 bp) peptidase genes were isolated. These were cloned into a GFP-expression vector for biolistic transformation of schistosomes. Both fragments promoted expression of GFP that was localised in the gut for SmCF and tegument for SmCB2, consistent with previous immunochemical data. Promoter-deletion of the SmCF gene indicated the importance of one or more transcription factor binding sites in the first 169 bp for both GFP-expression and its tissue specificity.

Animals↗
PubMed2006

Leishmania major metacaspase can replace yeast metacaspase in programmed cell death and has arginine-specific cysteine peptidase activity.

The human protozoan parasite Leishmania major has been shown to exhibit several morphological and biochemical features characteristic of a cell death program when differentiating into infectious stages and under a variety of stress conditions. Although some caspase-like peptidase activity has been reported in dying parasites, no caspase gene is present in the genome. However, a single metacaspase gene is present in L. major whose encoded protein harbors the predicted secondary structure and the catalytic dyad histidine/cysteine described for caspases and other metacaspases identified in plants and yeast. The Saccharomyces cerevisiae metacaspase YCA1 has been implicated in the death of aging cells, cells defective in some biological functions, and cells exposed to different environmental stresses. In this study, we describe the functional heterologous complementation of a S. cerevisiae yca1 null mutant with the L. major metacaspase (LmjMCA) in cell death induced by oxidative stress. We show that LmjMCA is involved in yeast cell death, similar to YCA1, and that this function depends on its catalytic activity. LmjMCA was found to be auto-processed as occurs for caspases, however LmjMCA did not exhibit any activity with caspase substrates. In contrast and similarly to Arabidopsis thaliana metacaspases, LmjMCA was active towards substrates with arginine in the P1 position, with the activity being abolished following H147A and C202A catalytic site mutations. These results suggest that metacaspases are members of a family of peptidases with a role in cell death conserved in evolution notwithstanding possible differences in their catalytic activity.

Animals↗
PubMed2006

The type II signal peptidase of Legionella pneumophila.

Legionella pneumophila is a facultative intracellular Gram-negative bacterium that has become an important cause of community-acquired and nosocomial pneumonia. Recent studies concerning the unravelling of bacterial virulence have suggested the involvement of protein secretion systems in bacterial pathogenicity. In this respect, the type II signal peptidase (LspA), which is specifically required for the maturation of lipoproteins, is of particular interest. This paper reports the cloning and functional characterization of the L. pneumophila lspA gene encoding the type II signal peptidase (SPase II). Activity of the L. pneumophila LspA was demonstrated using a globomycin sensitivity assay in Escherichia coli. In L. pneumophila, the lspA gene is flanked by the isoleucyl-tRNA synthetase (ileS) gene and the gene encoding a 2-hydroxy-3-deoxy-phosphogluconate aldolase. Although there is no apparent physiological connection, transcriptional analysis demonstrated that, as in some other Gram-negative bacteria, lspA is cotranscribed with ileS in L. pneumophila. Finally, in silico analysis revealed that several proteins known to be crucial for virulence and intracellular growth of L. pneumophila are predicted to be lipoproteins. These include, in particular, proteins involved in protein secretion and motility. Results obtained strongly suggest an important role for LspA in the pathogenicity of L. pneumophila, making it a promising new target for therapeutic intervention.

Amino Acid Sequence↗
PubMed2004

Immunization with C5a peptidase from either group A or B streptococci enhances clearance of group A streptococci from intranasally infected mice.

Group A streptococci (S. pyogenes) are responsible for pharyngitis, impetigo and several more serious diseases. Emergence of toxic shock, and necrotizing fasciitis, associated with this pathogen over the past 10 years, has generated interest in development of a vaccine, which would prevent infections and potential serious complications. The highly conserved C5a peptidase that is expressed on the surface of group A streptococcus and other streptococcal species, associated with human infections, is a prime vaccine candidate. Here, we report construction of an inactive form of the peptidase and test its potential to induce protection in mice from intranasal challenge with either serotype M1 and M49 strains of streptococci. Mice were immunized by subcutaneous administration of recombinant proteins, mixed with Alum and monophosphoryl lipid A (MPL) adjuvants. Control mice were vaccinated with tetanus toxoid in the same adjuvants. Preparations of SCPA protein were highly immunogenic in mice. Antibody directed against protein from either group A (SCPAw) or group B (SCPBw) streptococci neutralized activity associated with both enzymes. Streptococci were cleared from the oral-nasal mucosa of mice immunized with vaccine protein more rapidly than those immunized with tetanus toxoid. Moreover, immunization with either protein enhanced clearance of group A streptococci from the lung. These results suggest that parenteral vaccination with SCPBw protein will provide protection against infection by either group A or B streptococci.

Adhesins, Bacterial↗
PubMed2000

Interaction of viper venom serine peptidases with thrombin receptors on human platelets.

The serine peptidases, thrombocytin and PA-BJ, isolated from the venom of Bothrops atrox and Bothrops jararaca, respectively, induce platelet aggregation and granule secretion without clotting fibrinogen. The specific platelet aggregation activity of each enzyme was about 15 times lower than that of thrombin. This activity was blocked by monoclonal antibodies recognizing protease activated receptor 1 (PAR1) and by heparin, but not by hirudin nor thrombomodulin. Both enzymes induced calcium mobilization in platelets and desensitized platelets to the action of thrombin and the SFLLRN peptide. We compared the effect of thrombin, PA-BJ, and thrombocytin on the degradation of the soluble N-terminal domain of the PAR1 receptor. The major cleavage site by thrombin and both viper enzymes was Arg41-Ser42. In addition, a rapid cleavage of the peptide bond at Arg46-Asn47 by the viper enzymes was observed, resulting in the inactivation of the tethered ligand. PA-BJ and thrombocytin both cleaved at 41-42 and 46-47 peptide bonds, and fragment 42-103 disappeared rapidly. Both viper enzymes caused calcium mobilization in fibroblasts transfected with PAR4 and desensitized these cells to the thrombin action. In conclusion, both PAR1 and PAR4 mediate the effect of viper venom serine peptidases on platelets.

Amino Acid Sequence↗
PubMed2001

Tetrameric dipeptidyl peptidase I directs substrate specificity by use of the residual pro-part domain.

The crystal structure of mature dipeptidyl peptidase I reveals insight into the unique tetrameric structure, substrate binding and activation of this atypical papain family peptidase. Each subunit is composed of three peptides. The heavy and light chains form the catalytic domain, which adopts the papain fold. The residual pro-part forms a beta-barrel with the carboxylate group of Asp1 pointing towards the substrate amino-terminus. The tetrameric structure appears to stabilize the association of the two domains and encloses a 12700 A3 spherical cavity. The tetramer contains six chloride ions, one buried in each S2 pocket and two at subunit interfaces.

Animals↗
PubMed1998

Factors limiting display of foreign peptides on the major coat protein of filamentous bacteriophage capsids and a potential role for leader peptidase.

Many small peptides can be displayed on every copy of the major coat protein in recombinant filamentous bacteriophages but larger peptides can only be accommodated in hybrid virions mixed with wild-type protein subunits. A peptide insert of 12 residues capable of display at high copy number in a hybrid virion was found to be incapable of supporting recombinant virion assembly, a defect that could not be overcome by over-expressing leader peptidase in the same Escherichia coli cell. In contrast, over-expressing leader peptidase did increase the copy number of two 9-residue peptides that were poorly incorporated into hybrid virions. The factors that limit peptide display are varied and not restricted to the early stages of viral assembly.

Amino Acid Sequence↗
PubMed1985

Highly sensitive assay for PZ-peptidase activity by high-performance liquid chromatography.

A rapid and highly sensitive assay method for measuring PZ-peptidase activity in newborn rat brain is described. The method is based on monitoring the absorption at 320 nm of PZ-Pro-Leu enzymatically formed from the substrate, PZ-L-Pro-L-Leu-Gly-L-Pro-D-Arg, after separation by high-performance liquid chromatography using a reversed-phase column. This method is sensitive enough to measure PZ-Pro-Leu at concentrations as low as 5 pmol, and is able to make the column ready for the next injection within 10 min after the preceding injection. By using this method, PZ-peptidase activity was discovered in clonal osteoblastic cells derived from newborn mouse calvaria.

Animals↗
PubMed1997

Pulmonary C-fiber activation before and after peptidase inhibition in rats.

Inhibition of peptidases within the lungs not only potentiates the effects of neuropeptides released from C-fibers but also the effects of bradykinin and capsaicin both of which stimulate C-fibers. To determine if peptidase inhibition potentiates C-fiber activation, we challenged pulmonary C-fibers in rats with capsaicin or bradykinin before and after inhibition of neutral endopeptidase (NEP) or angiotensin converting enzyme (ACE). Inhibition of NEP by phosphoramidon (10 mg/kg, i.v.) potentiated the effect of capsaicin (0.5-1 micrograms, i.v.) on C-fiber activity but did not change the response to bradykinin (1-2 micrograms, i.v.). Inhibition of ACE by captopril (5 mg/kg, i.v.) potentiated C-fiber activation by either bradykinin or capsaicin. Aerosol administration of either phosphoramidon (1 x 10(-5) M, 2 min) or captopril (4.6 x 10(-3) M, 2 min) potentiated C-fiber activation by capsaicin aerosol (1.6 x 10(-4) M, 1 min) but not by bradykinin aerosol (9.4 x 10(-5) M, 1 min). Therefore, inhibition of NEP or ACE may potentiate airway obstructive mechanisms initiated by C-fiber stimulation.

Administration, Inhalation↗
PubMed1983

Microvillar peptidase activity in amniotic fluid: possible use in the prenatal diagnosis of cystic fibrosis.

The activities of two microvillar peptidases, gamma-glutamyl transpeptidase (GGTP) and aminopeptidase M (APM), have been measured in 132 samples of mid-trimester amniotic fluid. These included samples from 16 pregnancies at risk for cystic fibrosis. The activities of both peptidases were significantly below the normal range in amniotic fluids from the 6 affected pregnancies. This points to early pathological changes in fetal tissues in which microvilli are prominent. In contrast, 4-methylumbelliferylguanidinobenzoate-reactive protease activity in amniotic fluid from the 6 affected pregnancies was normal. Correlation of individual values between GGTP and APM was close in all cases examined, so that when a further 7 samples from cases at risk became available they were tested for GGTP alone. Of these, the 3 affected pregnancies had significantly reduced GGTP activity, particularly in the early weeks of gestation. It is suggested that early amniocentesis and examination of gamma-glutamyl-transpeptidase isoenzyme constitution might make possible the reliable early diagnosis of cystic fibrosis.

Aminopeptidases↗