Published by De Gruyter

Volume 389 Issue 8

Issue of Biological Chemistry

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Contents
Journal Overview

Editors' Note

August 28, 2008

Editors' Note

Helmut Sies, Hans Fritz

Page range: 963-963

Editorial

August 28, 2008

Farewell to Hans Fritz, Executive Editor

Helmut Sies

Page range: 965-965

Guest Editorial

August 28, 2008

Highlight on Advances in Proteolysis Research

Georgia Sotiropoulou, Christian P. Sommerhoff

Page range: 967-969

Highlight: 5^th General Meeting of the International Proteolysis Society 2007

August 19, 2008

Proteinases as hormones: targets and mechanisms for proteolytic signaling

Kristina K. Hansen, Katerina Oikonomopoulou, Amos Baruch, Rithwik Ramachandran, Paul Beck, Eleftherios P. Diamandis, Morley D. Hollenberg

Page range: 971-982

Abstract

Proteinases, such as kallikrein-related peptidases, trypsin and thrombin, can play hormone-like ‘messenger’ roles in vivo . They can regulate cell signaling by cleaving and activating a novel family of G-protein-coupled proteinase-activated receptors (PARs 1–4) by unmasking a tethered receptor-triggering ligand. Short synthetic PAR-derived peptide sequences (PAR-APs) can selectively activate PARs 1, 2 and 4, causing physiological responses in vitro and in vivo . Using the PAR-APs to activate the receptors in vivo , it has been found that PARs, like hormone receptors, can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (central and peripheral). PARs trigger responses ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased nociception. These PAR-stimulated responses have been implicated in various disease states, including cancer, atherosclerosis, asthma, arthritis, colitis and Alzheimer's disease. In addition to targeting the PARs, proteinases can also cause hormone-like effects by other signaling mechanisms that may be as important as the activation of PARs. Thus, the PARs themselves, their activating serine proteinases and their signaling pathways can be considered as attractive targets for therapeutic drug development. Further, proteinases can be considered as physiologically relevant ‘hormone-like’ messengers that can convey signals locally or systemically either via PARs or by other mechanisms.

August 19, 2008

Glutaminyl cyclases from animals and plants: a case of functionally convergent protein evolution

Stephan Schilling, Claus Wasternack, Hans-Ulrich Demuth

Page range: 983-991

Abstract

Several mammalian peptide hormones and proteins from plant and animal origin contain an N-terminal pyroglutamic acid (pGlu) residue. Frequently, the moiety is important in exerting biological function in either mediating interaction with receptors or stabilizing against N-terminal degradation. Glutaminyl cyclases (QCs) were isolated from different plants and animals catalyzing pGlu formation. The recent resolution of the 3D structures of Carica papaya and human QCs clearly supports different evolutionary origins of the proteins, which is also reflected by different enzymatic mechanisms. The broad substrate specificity is revealed by the heterogeneity of physiological substrates of plant and animal QCs, including cytokines, matrix proteins and pathogenesis-related proteins. Moreover, recent evidence also suggests human QC as a catalyst of pGlu formation at the N-terminus of amyloid peptides, which contribute to Alzheimer's disease. Obviously, owing to its biophysical properties, the function of pGlu in plant and animal proteins is very similar in terms of stabilizing or mediating protein and peptide structure. It is possible that the requirement for catalysis of pGlu formation under physiological conditions may have triggered separate evolution of QCs in plants and animals.

August 19, 2008

Alternative pathways for production of β-amyloid peptides of Alzheimer's disease

Vivian Hook, Israel Schechter, Hans-Ulrich Demuth, Gregory Hook

Page range: 993-1006

Abstract

This highlight article describes three Alzheimer's disease (AD) studies presented at the 5 th General Meeting of the International Proteolysis Society that address enzymatic mechanisms for producing neurotoxic β-amyloid (Aβ) peptides. One group described the poor kinetics of BACE 1 for cleaving the wild-type (WT) β-secretase site of APP found in most AD patients. They showed that cathepsin D displays BACE 1-like specificity and cathepsin D is 280-fold more abundant in human brain than BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the WT β-secretase site, they suggested continuing the search for additional β-secretase(s). The second group reported cathepsin B as an alternative β-secretase possessing excellent kinetic efficiency and specificity for the WT β-secretase site. Significantly, inhibitors of cathepsin B improved memory, with reduced amyloid plaques and decreased Aβ(40/42) in brains of AD animal models expressing amyloid precursor protein containing the WT β-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Aβ. Results showed that cathepsin B, but not BACE 1, efficiently cleaves the WT β-secretase isoaspartate site. Furthermore, cyclization of N-terminal Glu by glutaminyl cyclase generates highly amyloidogenic pGluAβ(3–40/42). These presentations suggest cathepsin B and glutaminyl cyclase as potential new AD therapeutic targets.

August 19, 2008

Bauhinia Kunitz-type proteinase inhibitors: structural characteristics and biological properties

Maria Luiza Vilela Oliva, Misako Uemura Sampaio

Page range: 1007-1013

Abstract

Plant proteinase inhibitors are involved in the regulation of the activity of many proteinases and, in consequence, in biological processes driven by proteolysis. In this review, we summarize recent results on the activity of native Bauhinia inhibitors and synthetic derivatives. Structural and functional characteristics and the potential therapeutic use of these inhibitors are also discussed.

August 19, 2008

Angiotensin-converting enzyme limits inflammation elicited by Trypanosoma cruzi cysteine proteases: a peripheral mechanism regulating adaptive immunity via the innate kinin pathway

Julio Scharfstein, Ana Carolina Monteiro, Veronica Schmitz, Erik Svensjö

Page range: 1015-1024

Abstract

Tissue injury by pathogens induces a stereotyped inflammatory response that alerts the innate immune system of the potential threat to host integrity. Here, we review knowledge emerging from investigations of the role of the kinin system in the mechanisms that link innate to the adaptive phase of immunity. Progress in this field started with results demonstrating that bradykinin is an endogenous danger signal that induces dendritic cell (DC) maturation via G protein-coupled bradykinin B 2 receptors (B 2 R). The immunostimulatory role of kinins was recently confirmed in two different mouse models of Trypanosoma cruzi infection, a parasitic protozoan equipped with kinin-releasing cysteine proteases (cruzipain). Infection by the intraperitoneal route showed that DCs from B 2 R -/- mice (susceptible phenotype) failed to sense kinin ‘danger’ signals proteolytically released by parasites, explaining why these mutant mice display lower frequencies of interferon-γ-producing effector T-cells. Studies of the dynamics of inflammation in the subcutaneous model of infection revealed that the balance between cruzipain and angiotensin-converting enzyme, respectively acting as kinin-generating and degrading enzymes, governs extent of DC maturation and T H 1 development via the B 2 R-dependent innate pathway. Studies of the kinin role in immunity may shed light on the relationship between proteolytic networks and the cytokine circuits that guide T-cell development.

August 19, 2008

How Na⁺ activates thrombin – a review of the functional and structural data

James A. Huntington

Page range: 1025-1035

Abstract

Thrombin is the ultimate coagulation factor; it is the final protease generated in the blood coagulation cascade and is the effector of clot formation. Regulation of thrombin activity is thus of great relevance to determining the correct haemostatic balance, with dysregulation leading to bleeding or thrombosis. One of the most enigmatic and controversial regulators of thrombin activity is the monovalent cation Na + . When bound to Na + , thrombin adopts a ‘fast’ conformation which cleaves all procoagulant substrates more rapidly, and when free of Na + , thrombin reverts to a ‘slow’ state which preferentially activates the protein C anticoagulant pathway. Thus, Na + -binding allosterically modulates the activity of thrombin and helps determine the haemostatic balance. Over the last 30 years, there has been much research investigating the structural basis of thrombin allostery. Biochemical and mutagenesis studies established which regions and residues are involved in the slow→fast conformational change, and recently several crystal structures of the putative slow form have been solved. In this article, the biochemical and crystallographic data are reviewed to see if we are any closer to understanding the conformational basis of the Na + activation of thrombin.

August 19, 2008

Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle

Elena Roza Motrescu, Marie-Christine Rio

Page range: 1037-1041

Abstract

This brief review focuses on the emerging role of matrix metalloproteinase 11 (MMP-11) in cancer progression. It has recently been shown that MMP-11 is induced in adipose tissue by cancer cells as they invade their surrounding environment. MMP-11 negatively regulates adipogenesis by reducing pre-adipocyte differentiation and reversing mature adipocyte differentiation. Adipocyte dedifferentiation in turn leads to the accumulation of non-malignant peritumoral fibroblast-like cells, which favor cancer cell survival and tumor progression. This MMP-11-mediated bi-directional cross-talk between invading cancer cells and adjacent adipocytes/pre-adipocytes highlights the central role that MMP-11 plays during tumor desmoplasia and represents a molecular link between obesity and cancer.

August 19, 2008

Isoaspartate residues dramatically influence substrate recognition and turnover by proteases

Livia Böhme, Joachim Wolfgang Bär, Torsten Hoffmann, Susanne Manhart, Hans-Henning Ludwig, Fred Rosche, Hans-Ulrich Demuth

Page range: 1043-1053

Abstract

Posttranslational modifications influence the structure, stability and biological activity of proteins. Most of the reactions are enzyme-catalyzed, but some, such as asparagine (Asn) and glutamine (Gln) deamidation and the isoaspartate (isoAsp) formation within peptide chains, occur spontaneously. It has been previously shown that certain peptide sequences form isoAsp quite fast if the Asp stretches are exposed to the protein surface, thereby potentially changing susceptibility to proteolysis at these sites. This tempted us to investigate the activity of exo- and endopeptidases against Asp- or isoAsp-containing substrates. Members of the prolyl oligopeptidase family were unable to cleave substrates after proline if isoAsp was placed in the P 2 -position. Caspases, usually accepting Asp at P 1 -position of their substrates, did not cleave isoAsp-containing sequences. Similarly, the metal-dependent aminopeptidase amino peptidase N did not turnover N-terminal isoAsp-containing substrates, nor could the endopeptidase matrix metalloproteinase 3 (MMP 3) hydrolyze a serum amyloid A protein-like substrate if the sequence contained isoAsp instead of Asp. Also, the highly specific enterokinase, usually clipping after a stretch of four Asp residues and a lysine in the P 1 position, could not turnover substrates if the P 2 amino acid was replaced by isoAsp. In contrast, acylamino acid-releasing enzyme and dipeptidyl peptidases 1, 2 and 4 hydrolyzed substrates containing the isoAsp-Ala motif.

August 19, 2008

Isoaspartate-containing amyloid precursor protein-derived peptides alter efficacy and specificity of potential β-secretases

Livia Böhme, Torsten Hoffmann, Susanne Manhart, Raik Wolf, Hans-Ulrich Demuth

Page range: 1055-1066

Abstract

Neuritic plaques of Alzheimer patients are composed of multiple protein components. Among them, the amyloid β-peptides (Aβ) 1–40/42 and further N- and C-terminally modified fragments of Aβ are highly abundant. Most prominent are the isoaspartate (isoAsp)-Aβ peptides and pyroglutamyl (pGlu)-Aβ. While pGlu-Aβ can only be formed from an N-terminal glutamate by glutaminyl cyclase, spontaneous isoAsp-isomerization cannot occur at an N-terminal aspartate of peptides. This means that isoAsp-Aβ formation must precede proteolysis of the amyloid precursor protein (APP). Aβ generation from APP by β- and γ-secretases initiates the amyloid peptide aggregation and deposition process. Two aspartate proteases have been identified as secretases: BACE-1 (β-site amyloid precursor protein cleaving enzyme) and the intramembrane γ-secretase multiprotein complex. However, recent evidence supports more than one β-secretase initiating this cascade. Formation of Aβ1–40/42 was predominantly studied by expression of mutated human APP sequences in cell culture and transgenic animals, generating Aβ fragments that did not contain such multiple posttranslational modifications as in Alzheimer's disease. This prompted us to investigate the catalytic turnover of Asp- or isoAsp-containing APP-derived peptide sequences by BACE-1 and cathepsin B, another potential β-secretase. While cathepsin B is more effective than BACE-1 in processing the Asp-containing peptide derivatives, only cathepsin B can cleave the isoAsp-containing peptides, which occurs with high catalytic efficiency.

August 19, 2008

Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model

Uta Schurigt, Lisa Sevenich, Corinne Vannier, Mieczyslaw Gajda, Anne Schwinde, Fee Werner, Andreas Stahl, Dominik von Elverfeldt, Anne-Katrin Becker, Matthew Bogyo, Christoph Peters, Thomas Reinheckel

Page range: 1067-1074

Abstract

Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.

August 19, 2008

Metastasis-associated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17

Cary W. Esselens, Jordi Malapeira, Núria Colomé, Marcia Moss, Francesc Canals, Joaquín Arribas

Page range: 1075-1084

Abstract

Metalloproteases play a complex role in tumor progression. While the activity of some ADAM, ADAMTS and matrix metalloproteases (MMPs) seems to be protumorigenic, the activity of others seems to prevent tumor progression. The identification of the array of substrates of a given metalloprotease (degradome) seems an adequate approach to predict the effect of the inhibition of a metalloprotease in tumors. Here, we present the proteomic identification of a novel substrate for ADAM10 and -17. We used SILAC (Stable Isotope Labeling by Amino acids in Cell culture), a proteomic technique based on the differential metabolic labeling of cells in different conditions. This was applied to MCF7 cells derived from an invasive mammary tumor, and the same cells expressing shRNAs that knock down ADAM10 or -17. Following this approach, we have identified C4.4A as a substrate to both metalloproteases. Since C4.4A is likely involved in tumor invasion, these results indicate that the cleavage of C4.4A by ADAM10 and ADAM17 contributes to tumor progression.

August 19, 2008

Intestine-specific expression of green fluorescent protein-tagged cathepsin B: proof-of-principle experiments

Kristina Mayer, Maria E. Iolyeva, Ulf Meyer-Grahle, Klaudia Brix

Page range: 1085-1096

Abstract

We hypothesized that tissue-specific expression of cathepsin B-enhanced green fluorescent protein (CB-EGFP) can be driven by the A33-antigen promoter that contains positive cis -regulatory elements, including caudal-related homeobox (CDX) binding sites. The intestine-specific transcription factor Cdx1 is crucial for A33-antigen promoter activation and could thereby induce expression of CB-EGFP. This concept was tested by construction of the vector pA33-CathB-EGFP encoding CB-EGFP downstream of the A33-antigen promoter. Its Cdx1 dependence, as an indication of its intestine-specific expression, was tested in Cdx1-negative CHO-K1 cells. Cdx1 expression was achieved upon transfection with pCdx1-DsRed-Express and was indicated by red fluorescence of the simultaneously translated reporter protein. Immunolabeling with Cdx1-specific antibodies showed correct targeting of the transcription factor to its point of action in nuclei of transfected cells. Co-transfection experiments with plasmids pA33-CathB-EGFP and pCdx1-DsRed-Express confirmed the hypothesis that Cdx1 indeed activates CB-EGFP expression in a manner dependent on the A33-antigen promoter. Co-localization with compartment-specific markers and subcellular fractionation confirmed CB-EGFP trafficking along the expected route to endolysosomal compartments. Hence, the A33-antigen promoter represents a potent tool for induction of Cdx1-dependent CB-EGFP expression in vitro . Our proof-of-principle studies confirm the suitability of this approach in visualizing protease transport in Cdx1-positive tissues of the gastrointestinal tract.

August 19, 2008

Substrate specificity determination of mouse implantation serine proteinase and human kallikrein-related peptidase 6 by phage display

Navneet Sharma, Katerina Oikonomopoulou, Kenichi Ito, Bernard Renaux, Eleftherios P. Diamandis, Morley D. Hollenberg, Derrick E. Rancourt

Page range: 1097-1105

Abstract

We constructed a random library of hexapeptides displayed on the surface of bacteriophage T7 to determine the substrate specificity of proteinases. The phage-displayed library was subjected to repeated rounds of biopanning with native implantation serine proteinase and recombinant human kallikrein-related peptidase 6 (KLK6) followed by selection and identification of putative substrates. For both enzymes, the results obtained demonstrate a preference for arginine and lysine at multiple positions in the recognition cleavage motif, confirming their previously reported trypsin-like substrate specificity. In the case of KLK6, there is also a pronounced presence of tryptophan within the cleaved peptide sequences, indicating its potential dual substrate specificity, acting as both a trypsin and chymotrypsin-like enzyme.

August 19, 2008

In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells

Sinisa Urban, Rosanna P. Baker

Page range: 1107-1115

Abstract

Intramembrane proteases hydrolyze peptide bonds within cell membranes. Recent crystal structures revealed that rhomboid intramembrane proteases contain a hydrated active site that opens to the outside of the cell, but is protected laterally from membrane lipids by protein segments. Using Escherichia coli rhomboid (GlpG) structures as a guide, we previously took a mutational approach to identify the GlpG gating mechanism that allows substrates to enter the active site laterally from the membrane. Mutations that weaken contacts keeping the gate closed increase enzyme activity and implicate transmembrane segment 5 as the substrate gate. Since these analyses were performed in vitro with pure proteins in detergent micelles, we have now examined GlpG in its natural environment, within the membrane of live E. coli cells. In striking congruity with in vitro analysis, gate-opening mutants in transmembrane segment 5 display up to a 10-fold increase in protease activity in living cells. Conversely, mutations in other parts of the protease, including the membrane-inserted L1 loop previously thought to be the gate, decrease enzyme activity. These observations provide evidence for the existence of both closed and open forms of GlpG in cells, and show that inter-conversion between them via substrate gating is rate limiting physiologically.

August 19, 2008

Human monocytes augment invasiveness and proteolytic activity of inflammatory breast cancer

Mona Mostafa Mohamed, Dora Cavallo-Medved, Bonnie F. Sloane

Page range: 1117-1121

Abstract

Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, and here, we examined in vitro the interactions between the human IBC cell line SUM149 and U937 human naive monocytes. We found an altered morphology, enhanced invasiveness and proteolytic activity of SUM149 cells when cultured with U937 cells or in U937-conditioned media (U937-CM). Increases in expression and activity of the cysteine protease cathepsin B and expression of caveolin-1 were also detected in SUM149 cells grown in U937-CM, thus suggesting a contribution of these proteins to the augmented invasion through and proteolysis of the extracellular matrix by the IBC cells.

August 19, 2008

Regulation of cathepsin K activity by hydrogen peroxide

Emmanuel Godat, Virginie Hervé-Grépinet, Florian Veillard, Fabien Lecaille, Maya Belghazi, Dieter Brömme, Gilles Lalmanach

Page range: 1123-1126

Abstract

Although cysteine cathepsins, including cathepsin K, are sensitive to oxidation, proteolytically active forms are found at inflammatory sites. Regulation of cathepsin K activity was analyzed in the presence of H 2 O 2 to gain an insight into these puzzling observations. H 2 O 2 impaired processing of procathepsin K and inactivated its mature form in a time- and dose-dependent mode. However, as a result of the formation of a sulfenic acid, as confirmed by trapping in the presence of 7-chloro-4-nitrobenzo-2-oxa-1,3-diazol, approximately one-third of its initial activity was restored by dithiothreitol. This incomplete inactivation may partially explain why active cysteine cathepsins are still found during acute lung inflammation.

Protein Structure and Function

August 19, 2008

Contribution of the C30/C75 disulfide bond to the biological properties of onconase

Gerard Torrent, Antoni Benito, Jessica Castro, Marc Ribó, Maria Vilanova

Page range: 1127-1136

Abstract

Onconase, a member of the pancreatic type ribonuclease family, is currently used as a chemotherapeutic agent for the treatment of different types of cancer. It is widely accepted that one of the properties that renders this enzyme cytotoxic is its ability to evade the cytosolic ribonuclease inhibitor (RI). In the present work, we produced and characterized an onconase variant that lacks the disulfide bond C30/C75. This variant mimics the stable unfolding intermediate des(30–75) produced in the reductive unfolding pathway of onconase. We found that the reduction of the C30/C75 disulfide bond does not significantly alter the cytotoxic properties of onconase, although the variant possesses a notably reduced conformational stability. Interestingly, both its catalytic activity and its ability to evade RI are comparable to wild-type onconase under mild reductive conditions in which the three disulfide containing intermediate des(30–75) is present. These results suggest that the C30/C75 disulfide bond could easily be reduced under physiological redox conditions.

August 19, 2008

Conformational changes in bovine lactoferrin induced by slow or fast temperature increases

Waleska D. Schwarcz, Lorena Carnelocce, Jerson L. Silva, Andréa C. Oliveira, Rafael B. Gonçalves

Page range: 1137-1142

Abstract

Lactoferrin (LF) is an iron-binding protein present in several secreted substances, such as milk, and has broad antimicrobial and physiological properties. Because high temperatures may affect protein stability and its functional properties, we investigated the effect of heat on bovine LF structure and stability. The effects of temperatures used during the pasteurization process on LF and its relationship to protein functionality were studied. Conformational changes were monitored using spectroscopic techniques, such as circular dichroism (CD) and fluorescence spectroscopy. The CD data at 70°C showed that LF's secondary structure is drastically and irreversibly affected when the temperature is gradually increased. The same effect is observed when the temperature is gradually raised from 25°C to 105°C and changes are monitored by tryptophan fluorescence emission. We also verified the effects of simulating the pasteurization process; LF remained well structured during the entire process and this result was not time-dependent. Owing to preservation of the secondary structure with changes in the tertiary structure, we thus believe that pasteurization might cause LF to change into an intermediate partially folded state. A better understanding of heat stability is important for the use of LF as a bioactive component in food.

About this journal

Objective
Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences.

Topics

general biochemistry
pathobiochemistry
structural biology
molecular and cellular biology
genetics and epigenetics
molecular medicine
cancer research
virology
immunology
plant molecular biology and biochemistry
novel experimental methodologies

Article formats
Research Articles, Short Communications, Reviews and Minireviews
Reviews are published by invitation only, but suggestions to the Editor-in-Chief are welcome.

The journal is associated with the German Society for Biochemistry and Molecular Biology (GBM).

Volume 389 Issue 8

Issue of Biological Chemistry

Editors' Note

Farewell to Hans Fritz, Executive Editor

Highlight on Advances in Proteolysis Research

Proteinases as hormones: targets and mechanisms for proteolytic signaling

Abstract

Glutaminyl cyclases from animals and plants: a case of functionally convergent protein evolution

Abstract

Alternative pathways for production of β-amyloid peptides of Alzheimer's disease

Abstract

Bauhinia Kunitz-type proteinase inhibitors: structural characteristics and biological properties

Abstract

Angiotensin-converting enzyme limits inflammation elicited by Trypanosoma cruzi cysteine proteases: a peripheral mechanism regulating adaptive immunity via the innate kinin pathway

Abstract

How Na+ activates thrombin – a review of the functional and structural data

Abstract

Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle

Abstract

Isoaspartate residues dramatically influence substrate recognition and turnover by proteases

Abstract

Isoaspartate-containing amyloid precursor protein-derived peptides alter efficacy and specificity of potential β-secretases

Abstract

Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model

Abstract

Metastasis-associated C4.4A, a GPI-anchored protein cleaved by ADAM10 and ADAM17

Abstract

Intestine-specific expression of green fluorescent protein-tagged cathepsin B: proof-of-principle experiments

Abstract

Substrate specificity determination of mouse implantation serine proteinase and human kallikrein-related peptidase 6 by phage display

Abstract

In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells

Abstract

Human monocytes augment invasiveness and proteolytic activity of inflammatory breast cancer

Abstract

Regulation of cathepsin K activity by hydrogen peroxide

Abstract

Contribution of the C30/C75 disulfide bond to the biological properties of onconase

Abstract

Conformational changes in bovine lactoferrin induced by slow or fast temperature increases

Abstract

How Na⁺ activates thrombin – a review of the functional and structural data