DOCSLIB.ORG

Catalytic Properties of the Caspases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Catalytic Properties of the Caspases Cell Death and Differentiation (1999) 6, 1054 ± 1059 ã 1999 Stockton Press All rights reserved 13509047/99 $15.00 http://www.stockton-press.co.uk/cdd Review Catalytic properties of the caspases HR Stennicke1 and GS Salvesen*,1 bond hydrolase, and includes endopeptidases and exopepti- dases. Caspases are strict endopeptidases. From a mechan- 1 The Program for Apoptosis and Cell Death Research, The Burnham Institute, istic point of view most proteases utilize their ability to force the 10901 North Torrey Pines Road, La Jolla, California, CA92037, USA trigonal planar peptide bond into a tetrahedal geometry as a * Corresponding author: GS Salvesen, The Program for Apoptosis and Cell prerequisite for hydrolysis. Thus, the majority of the available Death Research, The Burnham Institute, 10901 North Torrey Pines Road, La binding energy is used for stabilizing this tetrahedral Jolla, California, CA 92037, USA. Tel: +1 (619) 646 3114; Fax: +1 (619) 646 3189; E-mail: [email protected] intermediate rather than merely forming an enzyme-substrate complex. The ability to catalyze the hydrolysis of the peptide Received 20.5.99; accepted 21.9.99 bond at neutral pH and ambient temperatures therefore Edited by D Nicholson characterizes proteases, where various catalytic mechanisms are located in a variety of otherwise unrelated protein scaffolds. At least five distinct catalytic mechanisms have been Abstract discovered in proteases, but irrespective of the type of Caspase stands for cysteine-dependent aspartate specific residues involved in the particular mechanisms, the key protease, and is a term coined to define proteases related to features are identical. About the point in the reaction coordinate where the enzyme pulls the peptide bond into interleukin 1b converting enzyme and CED-3.1 Thus their tetrahedral geometry, a nucleophile adds to the carbonyl enzymatic properties are governed by a dominant specificity carbon of the scissile bond. In some families of proteases (the for substrates containing Asp, and by the use of a Cys side- metallo- and aspartic protease classes) this is simply done by chain for catalyzing peptide bond cleavage. The use of a Cys making a water molecule nucleophilic through specific side chain as a nucleophile during peptide bond hydrolysis is interactions to groups in the protease. In others (the common to several protease families. However, the primary cysteine, serine, and threonine protease classes) a side- specificity for Asp turns out to be very rare among protease chain within the protease acts as the nucleophile, forming a families throughout biotic kingdoms. Of all known mammalian covalent adduct (an ester) with the substrate during catalysis. proteases only the caspase activator granzyme B, a serine Hydrolysis of substrate by these latter classes occurs by protease, has the same primary specificity. In addition to this displacement of the ester. The second step in peptide bond unusual primary specificity, caspases are remarkable in that hydrolysis is the protonation of the a-amino moiety of the leaving group, which is particularly important in cysteine certain of their zymogens have intrinsic proteolytic activity. proteases such as the caspases due to the lower stability of This latter property is essential to trigger the proteolytic the thiol ester intermediate compared to regular esters. pathways that lead to apoptosis. Here we review the known In the case of the caspases it is the formation of a enzymatic properties of the caspases and their zymogens tetrahedral intermediate by promotion of a cysteine residue within the broad context of structure:mechanism:activity to act as a nucleophile that is the pivotal point in catalysis relationships of proteases in general. and thus, we will focus on this particular mechanism for promoting hydrolysis. The organization of the catalytic site, Keywords: protease; proteolysis; catalytic mechanism; caspase the geometry of the residues, and the distance between them, all have a variety of implications for protease Abbreviations: AMC, 7-amino-ymethyl-coumarin; +PA, tissue functions in vivo. This particular point becomes very clear plasminogen activator when comparing two proteases that uses the same catalytic machinery to promote the breakage of the peptide bond, but on quite different scaffolds as it is the case for the caspase family and the papain family. Though they use Breaking the peptide bond essentially the same catalytic mechanism, these two The emergence of amino acids as the building blocks of families of cysteine proteases have some very significant proteins allows for the combination of stability, strength, and differences in the promotion of catalysis as well as the structural features unique to the peptide bond. However, this organization of the substrate binding site. strength and stability of the peptide bond also makes specific cleavage or degradation of proteins by hydrolysis much more Catalytic mechanism than a simple `just add water' problem. This is evident from the fact that non-catalyzed hydrolysis of proteins requires Like other cysteine proteases, the caspases contain a prolonged heating even in the presence of strong acids. catalytic Cys-His pair with Cys285 acting as the nucleophile Thus, enzymes that cleave peptide bonds (peptidases or and His237 acting as the general base to abstract the proton proteases) have high energy barriers to overcome. The term from the catalytic Cys and promote the nucleophile (Figure 1). protease is synonymous with peptidase, meaning peptide The numbering of caspase residues follows the caspase 1 Catalytic properties of the caspases HR Stennicke and GS Salvesen 1055 3 convention. Interestingly, serine proteases (such as trypsin, drop in kcat. In the caspases this third component of the tissue plasminogen activator, and subtilisin) also frequently catalytic triad is not a side-chain, but rather is proposed to be contain a His residue that accompanies the catalytic Ser. In the backbone carbonyl group of residue 177, which in the model cysteine protease papain, where the cysteine caspase 1 is a proline and in caspase 3 a threonine.4,5 protease catalytic mechanism has been studied most Unfortunately, the importance of this third member is difficult extensively, it is believed that the Cys-His dyad exists as an to establish in the caspases since the interactions are to a ion-pair where the thiol proton of the catalytic Cys has been backbone moiety, which cannot easily be experimentally transferred to the acceptor His before substrate binding.2 Pre- verified by mutagenesis. Furthermore, alignment of the polarization of the catalytic nucleophile represents one of the known mammalian caspases (Accession PF00656)6 does major differences between the serine and cysteine proteases, not reveal any significant conservation in the region since in the serine proteases the nucleophile is believed to surrounding the putative third member of the triad, allowing develop along the reaction coordinate. While the ability of the us to raise the hypothesis that the putative third member may catalytic His to abstract a proton from the catalytic Cys is not exist in the caspase structure and mechanism. extremely important, the ability to protonate the a-amino group Investigations of the pH dependence of caspase of the scissile bond is expected to be at least as important in catalysis have provided useful insights into the catalytic the caspases. The reason for the importance of the mechanism. Human caspases exhibit only minor differ- protonation of this group lies in the properties and reactivity ences in pH profiles, and all are maximally active within the of the thiol ester: its susceptibility to nucleophilic attack. Thus, pH range and ionic strength of cell cytosols.7,8 They all if the a-amino group is not protonated the reformation of the exhibit a rather narrow bell-shaped pH dependence with peptide bond will be favored over the release of the leaving optima in the range 6.8 ± 7.2 signifying the existence of one group, and consequently proteolysis will not occur. active form of the enzyme with the increase in activity most In many proteases the side-chain of a third residue plays a likely due to the de-protonation of the catalytic Cys residue. significant role in the promotion of catalysis. The majority of In this respect the caspases closely resemble other the members of the papain family contain an Asn side-chain unrelated cysteine proteases such as papain in their that is believed to orient the histidine in the Cys-His ion-pair, activity pH profiles although the pH-profile is much more thereby influencing catalysis.3 Indeed, when Asn175 is narrow than that found for papain.9 Interestingly, the replaced by an alanine in papain, the catalytic activity is substitution of the third member of the catalytic triad in decreased by more than 100-fold mainly due to a significant papain also results in a considerable narrowing of the pH profile due to the increased distance between the catalytic residues.3 This observation supports the lack of a third member of the catalytic triad in caspases since examination of the structure of papain complexed with leupeptin reveals a distance between the catalytic residues to be 3.75 AÊ ,10 which is significantly less than the distance of 5.2 AÊ found in the caspase:aldehyde structures.4,5 Interestingly, the large distance between catalytic Cys and His residues in caspase structures argues against an ion pair, with the implication that the Cys may not be pre-polarized. The substrate binding site The substrate binding site in all proteases is composed of a fairly large number of amino acid residues that secure proper alignment of the substrates prior to hydrolysis and help promote catalysis through stabilization of the transition state. The binding site is divided into a number of sub-sites (see Figure 2), each securing a single amino acid residue of the substrate by multiple interactions. In addition to interactions Figure 1 The minimal caspase catalytic site.
Load more

Recommended publications
  • Manner Via Caspase-8 in an RIP3
    Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1 β and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner This information is current as of October 2, 2021. Lukas Bossaller, Ping-I Chiang, Christian Schmidt-Lauber, Sandhya Ganesan, William J. Kaiser, Vijay A. K. Rathinam, Edward S. Mocarski, Deepa Subramanian, Douglas R. Green, Neal Silverman, Katherine A. Fitzgerald, Ann Marshak-Rothstein and Eicke Latz Downloaded from J Immunol 2012; 189:5508-5512; Prepublished online 9 November 2012; doi: 10.4049/jimmunol.1202121 http://www.jimmunol.org/content/189/12/5508 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/11/12/jimmunol.120212 Material 1.DC1 References This article cites 30 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/189/12/5508.full#ref-list-1 by guest on October 2, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved.
    [Show full text]
  • The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies
    Hindawi Publishing Corporation International Journal of Cell Biology Volume 2010, Article ID 215158, 21 pages doi:10.1155/2010/215158 Review Article TheRoleofCyclooxygenase-2inCellProliferationandCell Death in Human Malignancies Cyril Sobolewski,1 Claudia Cerella,1 Mario Dicato,1 Lina Ghibelli,2 and Marc Diederich1 1 LaboratoiredeBiologieMol´eculaire et Cellulaire du Cancer, Hopitalˆ Kirchberg, 9 rue Edward Steichen, 2540 Luxembourg, Luxembourg 2 Dipartimento di Biologia, Universita` di Roma di Roma Tor Vergata, Via Ricerca Scientifica snc, 00133 Rome, Italy Correspondence should be addressed to Marc Diederich, [email protected] Received 16 July 2009; Accepted 18 December 2009 Academic Editor: Simone Fulda Copyright © 2010 Cyril Sobolewski et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It is well admitted that the link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways, which act during the different steps of tumorigenesis. The cyclooxygenases (COXs) are a family of enzymes, which catalyze the rate-limiting step of prostaglandin biosynthesis. This family contains three members: ubiquitously expressed COX- 1, which is involved in homeostasis; the inducible COX-2 isoform, which is upregulated during both inflammation and cancer; and COX-3, expressed in brain and spinal cord, whose functions remain to be elucidated. COX-2 was described to modulate cell proliferation and apoptosis mainly in solid tumors, that is, colorectal, breast, and prostate cancers, and, more recently, in hematological malignancies. These findings prompt us to analyze here the effects of a combination of COX-2 inhibitors together with different clinically used therapeutic strategies in order to further improve the efficiency of future anticancer treatments.
    [Show full text]
  • Part One Amino Acids As Building Blocks
    Part One Amino Acids as Building Blocks Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.3 – Building Blocks, Catalysis and Coupling Chemistry. Edited by Andrew B. Hughes Copyright Ó 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32102-5 j3 1 Amino Acid Biosynthesis Emily J. Parker and Andrew J. Pratt 1.1 Introduction The ribosomal synthesis of proteins utilizes a family of 20 a-amino acids that are universally coded by the translation machinery; in addition, two further a-amino acids, selenocysteine and pyrrolysine, are now believed to be incorporated into proteins via ribosomal synthesis in some organisms. More than 300 other amino acid residues have been identified in proteins, but most are of restricted distribution and produced via post-translational modification of the ubiquitous protein amino acids [1]. The ribosomally encoded a-amino acids described here ultimately derive from a-keto acids by a process corresponding to reductive amination. The most important biosynthetic distinction relates to whether appropriate carbon skeletons are pre-existing in basic metabolism or whether they have to be synthesized de novo and this division underpins the structure of this chapter. There are a small number of a-keto acids ubiquitously found in core metabolism, notably pyruvate (and a related 3-phosphoglycerate derivative from glycolysis), together with two components of the tricarboxylic acid cycle (TCA), oxaloacetate and a-ketoglutarate (a-KG). These building blocks ultimately provide the carbon skeletons for unbranched a-amino acids of three, four, and five carbons, respectively. a-Amino acids with shorter (glycine) or longer (lysine and pyrrolysine) straight chains are made by alternative pathways depending on the available raw materials.
    [Show full text]
  • Molecular Markers of Serine Protease Evolution
    The EMBO Journal Vol. 20 No. 12 pp. 3036±3045, 2001 Molecular markers of serine protease evolution Maxwell M.Krem and Enrico Di Cera1 ment and specialization of the catalytic architecture should correspond to signi®cant evolutionary transitions in the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St Louis, history of protease clans. Evolutionary markers encoun- MO 63110-1093, USA tered in the sequences contributing to the catalytic apparatus would thus give an account of the history of 1Corresponding author e-mail: [email protected] an enzyme family or clan and provide for comparative analysis with other families and clans. Therefore, the use The evolutionary history of serine proteases can be of sequence markers associated with active site structure accounted for by highly conserved amino acids that generates a model for protease evolution with broad form crucial structural and chemical elements of applicability and potential for extension to other classes of the catalytic apparatus. These residues display non- enzymes. random dichotomies in either amino acid choice or The ®rst report of a sequence marker associated with serine codon usage and serve as discrete markers for active site chemistry was the observation that both AGY tracking changes in the active site environment and and TCN codons were used to encode active site serines in supporting structures. These markers categorize a variety of enzyme families (Brenner, 1988). Since serine proteases of the chymotrypsin-like, subtilisin- AGY®TCN interconversion is an uncommon event, it like and a/b-hydrolase fold clans according to phylo- was reasoned that enzymes within the same family genetic lineages, and indicate the relative ages and utilizing different active site codons belonged to different order of appearance of those lineages.
    [Show full text]
  • Apoptotic Threshold Is Lowered by P53 Transactivation of Caspase-6
    Apoptotic threshold is lowered by p53 transactivation of caspase-6 Timothy K. MacLachlan*† and Wafik S. El-Deiry*‡§¶ʈ** *Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, and Departments of ‡Medicine, §Genetics, ¶Pharmacology, and ࿣Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Communicated by Britton Chance, University of Pennsylvania School of Medicine, Philadelphia, PA, April 23, 2002 (received for review January 11, 2002) Little is known about how a cell’s apoptotic threshold is controlled Inhibition of the enzyme reduces the sensitivity conferred by after exposure to chemotherapy, although the p53 tumor suppres- overexpression of p53. These results identify a pathway by which sor has been implicated. We identified executioner caspase-6 as a p53 is able to accelerate the apoptosis cascade by loading the cell transcriptional target of p53. The mechanism involves DNA binding with cell death proteases so that when an apoptotic signal is by p53 to the third intron of the caspase-6 gene and transactiva- received, programmed cell death occurs rapidly. tion. A p53-dependent increase in procaspase-6 protein level al- lows for an increase in caspase-6 activity and caspase-6-specific Materials and Methods Lamin A cleavage in response to Adriamycin exposure. Specific Western Blotting and Antibodies. Immunoblotting was carried out by inhibition of caspase-6 blocks cell death in a manner that correlates using mouse anti-human p53 monoclonal (PAb1801; Oncogene), with caspase-6 mRNA induction by p53 and enhances long-term rabbit anti-human caspase-3 (Cell Signaling, Beverly, MA), mouse survival in response to a p53-mediated apoptotic signal.
    [Show full text]
  • XIAP's Profile in Human Cancer
    biomolecules Review XIAP’s Profile in Human Cancer Huailu Tu and Max Costa * Department of Environmental Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA; [email protected] * Correspondence: [email protected] Received: 16 September 2020; Accepted: 25 October 2020; Published: 29 October 2020 Abstract: XIAP, the X-linked inhibitor of apoptosis protein, regulates cell death signaling pathways through binding and inhibiting caspases. Mounting experimental research associated with XIAP has shown it to be a master regulator of cell death not only in apoptosis, but also in autophagy and necroptosis. As a vital decider on cell survival, XIAP is involved in the regulation of cancer initiation, promotion and progression. XIAP up-regulation occurs in many human diseases, resulting in a series of undesired effects such as raising the cellular tolerance to genetic lesions, inflammation and cytotoxicity. Hence, anti-tumor drugs targeting XIAP have become an important focus for cancer therapy research. RNA–XIAP interaction is a focus, which has enriched the general profile of XIAP regulation in human cancer. In this review, the basic functions of XIAP, its regulatory role in cancer, anti-XIAP drugs and recent findings about RNA–XIAP interactions are discussed. Keywords: XIAP; apoptosis; cancer; therapeutics; non-coding RNA 1. Introduction X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3), baculoviral IAP repeat-containing protein 4 (BIRC4), and human IAPs like protein (hILP), belongs to IAP family which was discovered in insect baculovirus [1]. Eight different IAPs have been isolated from human tissues: NAIP (BIRC1), BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4), BIRC5 (survivin), BIRC6 (apollon), BIRC7 (livin) and BIRC8 [2].
    [Show full text]
  • Calpain Inhibitors Prevent Nitric Oxide-Triggered Excitotoxic Apoptosis
    Calpain inhibitors prevent nitric oxide- triggered excitotoxic apoptosis Christiane Volbracht,1,2 Eugenio Fava,1,3 Marcel Leist1,4 and Pierluigi Nicotera1,3,CA 1Molecular Toxicology, University of Konstanz, Konstanz, Germany; 2Institute of Molecular and Cell Biology, Singapore 117609, Singapore; 3MRC Toxicology Unit, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN; 4Department of Neurobiology, H. Lundbeck A/S, 2500 Valby, Denmark CACorresponding Author The pathogenesis of some neurodegenerative disorders has potential, chromatin breakdown, and subsequent death of been linked to excitotoxicity, excess generation of nitric oxide cerebellar granule neurons exposed to NO donors (S-nitroso- (NO) and apoptosis. Here, we used a model of NO-triggered L-glutathione, S-nitroso-N-acetyl-D,L-penicillamine, and diethy- neuronal apoptosis that was strictly dependent on autocrine lamino-diazenolate-2-oxide). Since inhibitors did not interfere 2 NMDA receptor (NMDA-R) activation and intracellular Ca with NMDA-R activation, we suggest that block of calpains increase. We investigated the ef®ciency and potentially bene- blunts NO-triggered neuronal apoptosis by stopping the ®cial effects of calpain inhibition. Three calpain inhibitors that cascade downstream of primary autocrine excitotoxic events. prevented intracellular fodrin proteolysis also blocked apopto- NeuroReport 12:3645±3648 & 2001 Lippincott Williams & tic features such as decrease in mitochondrial membrane Wilkins. Key words: Apoptosis; Calpains; Excitotoxicity; Mitochondria; Nitric oxide INTRODUCTION MATERIALS AND METHODS Massive generation of the pleiotropic messenger molecule Cell culture: Murine CGC were isolated from 8-day-old nitric oxide (NO) has been implicated in many neuro- speci®c pathogen free BALB/e mice obtained from the pathological conditions including ischemia [1].
    [Show full text]
  • Production of Circularly Permuted Caspase-2 for Affinity Fusion-Tag
    biomolecules Article Production of Circularly Permuted Caspase-2 for Affinity Fusion-Tag Removal: Cloning, Expression in Escherichia coli, Purification, and Characterization 1,2, 1,2, , 1,3 1,3 Monika Cserjan-Puschmann y , Nico Lingg * y , Petra Engele , Christina Kröß , Julian Loibl 1, Andreas Fischer 1, Florian Bacher 1, Anna-Carina Frank 1,2, Christoph Öhlknecht 1,4,Cécile Brocard 5, Chris Oostenbrink 1,4 , Matthias Berkemeyer 5, Rainer Schneider 1,3, Gerald Striedner 1,2 and Alois Jungbauer 1,2,* 1 ACIB-Austrian Centre of Industrial Biotechnology, Muthgasse 18, 1190 Vienna, Austria; [email protected] (M.C.-P.); [email protected] (P.E.); [email protected] (C.K.); [email protected] (J.L.); andreas.fi[email protected] (A.F.); fl[email protected] (F.B.); [email protected] (A.-C.F.); [email protected] (C.Ö.); [email protected] (C.O.); [email protected] (R.S.); [email protected] (G.S.) 2 Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria 3 Institute of Biochemistry, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria 4 Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Vienna, Muthgasse 18, 1190 Vienna, Austria 5 Biopharma Process Science Austria, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria; [email protected] (C.B.); [email protected] (M.B.) * Correspondence: [email protected] (N.L.); [email protected] (A.J.) These authors have contributed equally to the manuscript.
    [Show full text]
  • Serine Proteases with Altered Sensitivity to Activity-Modulating
    (19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants.
    [Show full text]
  • P53 and the Cathepsin Proteases As Co-Regulators of Cancer and Apoptosis
    cancers Review Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis Surinder M. Soond 1,*, Lyudmila V. Savvateeva 1, Vladimir A. Makarov 1, Neonila V. Gorokhovets 1, Paul A. Townsend 2 and Andrey A. Zamyatnin, Jr. 1,3,4,* 1 Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, 119991 Moscow, Russia; [email protected] (L.V.S.); [email protected] (V.A.M.); gorokhovets_n_v@staff.sechenov.ru (N.V.G.) 2 Division of Cancer Sciences and Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, and the NIHR Manchester Biomedical Research Centre, Manchester M13 9PL, UK; [email protected] 3 Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia 4 Department of Biotechnology, Sirius University of Science and Technology, 1 Olympic Ave, 354340 Sochi, Russia * Correspondence: [email protected] (S.M.S.); [email protected] (A.A.Z.J.) Received: 6 October 2020; Accepted: 19 November 2020; Published: 22 November 2020 Simple Summary: This article describes an emerging area of significant interest in cancer and cell death and the relationships shared by these through the p53 and cathepsin proteins. While it has been demonstrated that the p53 protein can directly induce the leakage of cathepsin proteases from the lysosome, directly triggering cell death, little is known about what factors set the threshold at which the lysosome can become permeabilized. It appears that the expression levels of cathepsin proteases may be central to this process, with some of them being transcriptionally regulated by p53.
    [Show full text]
  • The Role of Caspase-2 in Regulating Cell Fate
    cells Review The Role of Caspase-2 in Regulating Cell Fate Vasanthy Vigneswara and Zubair Ahmed * Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK; [email protected] * Correspondence: [email protected] Received: 15 April 2020; Accepted: 12 May 2020; Published: 19 May 2020 Abstract: Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life. Keywords: caspase-2; procaspase; apoptosis; splice variants; activation; intrinsic; extrinsic; neurons 1. Introduction Apoptosis, or programmed cell death (PCD), plays a pivotal role during embryonic development through to adulthood in multi-cellular organisms to eliminate excessive and potentially compromised cells under physiological conditions to maintain cellular homeostasis [1]. However, dysregulation of the apoptotic signaling pathway is implicated in a variety of pathological conditions. For example, excessive apoptosis can lead to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, whilst insufficient apoptosis results in cancer and autoimmune disorders [2,3]. Apoptosis is mediated by two well-known classical signaling pathways, namely the extrinsic or death receptor-dependent pathway and the intrinsic or mitochondria-dependent pathway.
    [Show full text]
  • BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer’S Disease Pathology
    Review BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer’s Disease Pathology Gerald Koelsch CoMentis, Inc., South San Francisco, CA 94080, USA; [email protected] Received: 15 September 2017; Accepted: 10 October 2017; Published: 13 October 2017 Abstract: Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder characterized by increasing loss in memory, cognition, and function of daily living. Among the many pathologic events observed in the progression of AD, changes in amyloid β peptide (Aβ) metabolism proceed fastest, and precede clinical symptoms. BACE1 (β-secretase 1) catalyzes the initial cleavage of the amyloid precursor protein to generate Aβ. Therefore inhibition of BACE1 activity could block one of the earliest pathologic events in AD. However, therapeutic BACE1 inhibition to block Aβ production may need to be balanced with possible effects that might result from diminished physiologic functions BACE1, in particular processing of substrates involved in neuronal function of the brain and periphery. Potentials for beneficial or consequential effects resulting from pharmacologic inhibition of BACE1 are reviewed in context of ongoing clinical trials testing the effect of BACE1 candidate inhibitor drugs in AD populations. Keywords: Alzheimer’s disease; amyloid hypothesis; BACE1; beta secretase; pharmacology 1. Introduction Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disorder, slowly eroding memory, cognition, and functions of daily living, inevitably culminating in death from pneumonia and infectious diseases resulting from failure to thrive, loss of fine motor skills, and incapacitation. Treatment is limited to therapeutics that alleviate symptoms of memory loss, but are effective for a relatively short duration during and after which disease progression continues.
    [Show full text]