Index

A metalloprotease domain, 304, 306 Abdominal aortic aneurysm. See substrates, 304, 305 Atherosclerosis and TIMP3, 304 ABPs. See Activity-based probes (ABPs) water molecule, 305 ACE. See Angiotensin-converting ADAM (ACE) ADAM10 and ADAM17, 303–304 Activated neutral proteinase (ANP), 225 domain structure, 303, 304 Activity-based probes (ABPs) in vivo function, 306–307 cysteine , 190, 191 mechanisms of activation, 311–313 human cancer tissues, 190–191 N-terminal signal sequence, 303 in vivo, 190, 191 shedding, health and disease, 308–309 metalloproteases, 191 structure, 307 MS analysis, 191 substrate recognition, 309–311 activity, 190 as therapeutic targets, 313 AD. See Alzheimer’s disease (AD) type I and II, 303 ADAM10, 303–304 ADAMs. See A disintegrin and ADAM and ADAM-TS proteases metalloprotease (ADAMs) amphiregulin, 503 ADAMTSs in angiogenesis adenocarcinoma cells, 444 inhibitors, 502 in arthritis, 449–450 osteoactivin, 502 3D structures in cancer, 501 CysR domain, 447–448 in inflammation and immunity Dis domain, 447 ADAM17, 504 M domain, 446–447 myeloid derived suppressor cell Sp domain, 448 (MDSC), 503 TS domain, 447 initiation, promotion and growth of tumors, endogenous inhibitors, 455–458 501–502 interglobular domain, 444 in invasion and metastasis, 503 non-catalytic domain, 448–449 as markers or therapeutic targets plasma causes, 445 ADAM17, 504 A disintegrin and metalloprotease (ADAMs) monoclonal antibody DN30, 504 in arthritis, 454–455 notch signaling, 501 3D structures TACE or tumor necrosis factor alpha CysR domain, 453 converting enzyme, 501 Dis domain, 453 ADAM17 expression EGF domain, 454 and ADAM10, 304 M domain, 452–453

K. Brix and W. Sto¨cker (eds.), Proteases: Structure and Function, 551 DOI 10.1007/978-3-7091-0885-7, © Springer-Verlag Wien 2013 552 Index

A disintegrin and metalloprotease (ADAMs) eukaryotic proteases, 235 (cont.) MEROPS database, 235 endogenous inhibitors, 455–458 modular composition proteolytic cleavage, 451 BTPs, 237–238 type I transmembrane , 450 C. elegans, 238 Aggrecanases. See ADAMTSs domain, 236–237 Alzheimer’s disease (AD) meprin subfamily, 237 APP, 319 pro-and catalytic domains, 238, 239 Aβ-degrading proteases N-terminal region, 242–243 ACE, 330 inhibitors, 246–247 IDE, 329 ovastacin, 251 MMP-2 and MMP-9, 329 zymogen structure and activation monomeric and fibrillar, 330 mechanism, 244–246 NEP and endothelin-converting Atherosclerosis , 328–329 blood vessel walls, 222 plasmin, 330 collagens and elastin, 223 β-and γ-secretase, 328 cystatin C, 223 description, 319 cysteine cathepsins, 223, 224 pathway, 319 extracellular matrix, 222 α-secretase, 320–321 GEMs, 223 β-secretase (see β-Secretase) macrophages, 223 γ-secretase, 326–328 Amyloid precursor protein (APP), 185 Angiotensin-converting enzyme (ACE), 33 B ANP. See Activated neutral proteinase (ANP) BACE1 (β-site APP cleaving enzyme), Apoptosome 322–325 cytochrome, 278–279 Blood brain barrier (BBB), 337 pro--9, 279 BMP1. See Bone morphogenetic protein protein Apaf-1, 279 1 (BMP1) APP. See Amyloid precursor protein (APP) BMP-1/tolloid-like proteases (BTPs) Arthritis cleavage sites, 247–248 ADAMs, 454–455 Drosophila tolloid, 248–249 ADAMTSs, 449–450 fibrillar procollagens, 247 cellular sources, 443 IGFBP3, 249 ECM-degrading proteinases, 443 lysyl oxidase, 249 potential candidate enzymes, 444 Bone morphogenetic protein 1 (BMP1), 236 Aspartic peptidases, 25–26 BTPs. See BMP-1/tolloid-like proteases Astacins (BTPs) active-site cleft and substrate specificity, 243–244 amphibians and fishes, 236 C BMP1, 236 CAD. See Caspase-activated DNAse (CAD) catalytic domains and metal binding sites -1/μ-calpain and calpain-2/m-calpain active-site helix, 238, 241–242 biological significance ‘cysteine-rich loop’, 241–242 brain injury, 401 polypeptide chain, 238, 239 regulation of physiological structure, 238, 240 processes, 399 zinc-binding region, 241 substrates in CNS system, 399 distribution and physiological role CNS injury, calpain-generated biomarkers BTPs, 247–249 compromised blood brain barrier crayfish astacin, 235–245, 437 (BBB), 402 hatching enzymes, 251–252 cytoskeletal structural protein human and mouse genomes, 247 aII-spectrin, 402 meprin, 249–251 CNS injury, calpain-target-based seminal fluid, 252 theranostics Index 553

acute brain injury, 402 skeletal-muscle-specific calpain, biomarkers, 403 405–409 calpain antagonists, advantage, 404 Carcinogenesis synthetic calpain inhibitors, 403 cystatin C, 220–221 theranostic approach, traumatic brain EGF-receptor, 220 injury, 404, 405 keratinocytes, 220 unique characteristics of calpain, 404 skin cancer, 220 discovery and nomenclature tumor promoters, 220 Ca 2+-activated neutral proteinase CARD. See Caspase activation and recruitment (CANP) activity, 397 domain (CARD) calpain-1 and calpain-2, 397 Cardiac homeostasis. See Cardiomyopathy , isoforms, 397 Cardiomyopathy calpastatin, 398 ANP, 225 neutral proteinase (CANP) activity, 397 L deficient mice, 224, 225 pathologic role echocardiographic investigations, 224 loss of intracellular calcium endosomal/lysosomal, 224 homeostasis, 400 macroautophagy, 224, 225 neuronal pathobiology, 400 Cardiovascular system structural features abdominal aortic aneurysm, 223–224 calpastatin, 399 cardiac homeostasis, 224–225 inactive proteases, 398 Caspase-activated DNAse (CAD), 284–285 multiple intramolecular sites, 398 Caspase activation and recruitment domain region/domains, 396, 398 (CARD), 281 Calpains in health and disease calpain-1, 395 activated initiator, 273–274 calpastatin, 395 architecture and substrate CAPN10 homologs recognition, 277–278 GLUT4 vesicle translocation, 415 , 275 OLETF, 415 morphology, 286–287 conventional calpains apoptosome, 278–279 brain injury, 401 catalytic domain, 272 calpain-1/μ-calpain and calpain- catalytic mechanism, 278 2/m-calpain, 397–405 ced-3 and 4, 270–271 in disease, 401 DARP, 291–293 human calpains, structures, 396 DISC, 279–280 other calpain members diseases, 293–294 Leishmania, 416 executioner, activation, 283 Trypanosoma, 416 family members, 270 PalB homologs FLIP, 290–291 Pal-PacC and Rim pathways, 414 α-helices, 275–276 processing of PacC, 413 human, 272–273 yeasts, 413 inflammasome, 280–281 phytocalpains in keratinocytes, 274 DEK1, 416 mammalian, 272 sugarcane expressed sequence, 416 in mammals, 274 SOL homologs, 415 NC-IUBMB, 271–272 TRA-3 homologs non-mammalian and metacaspases, CAPN6 proteins, 414 274–275 mammalian CAPN6, 415 regulation and specific inhibition, 288–289 unconventional calpains Rho-ROCK signaling pathway, 287–288 gastrointestinal-tract-specific calpains, substrates 410–413 CAD, 284–285 554 Index

hTERT, 285 M6P, 145–147 PARP, 285 non-lysosomal localization, 143–145 pro-interleukins and interleukins, N-terminal signal peptide, 140, 141 285–286 proteolytic processing, 142–143 ROCK 1, 284 Cathepsins tetrameric enzyme, 271 (see Cathepsin B) XIAP, 290 cathepsin D (see Cathepsin D) Catalytic mechanism, 23–24, 38, 180, 271, (see Cathepsin L) 278 cysteine (see Cysteine cathepsins) Cathepsin B in situ, 127 cancer cells, 138–139 lysosomal storage disorders, 157–158 chain enzymes, 136 M6P receptors, 128–130 disulfide bridges, 137 regulatory pathways, 127 extracellular forms, 139–140 Chain processing, cathepsin D HepG2 cells, 137 cysteine cathepsin inhibitors, 154 human tissues and cell lines, 136 double-chain processing, 154 lysosomal proteinase, 137–138 endosomal single-chain, 154 macrophages, 137 in vitro, 154 Cathepsin D psoriatic skin biopsies, 155 aspartyl proteinase, 149 Cleavage sites, PTMs biological fluids ABPs, 190–191 abnormal levels, 156 PICS, 189–190 cancer development and progression, potential protease substrates, 188 156–157 protease web, 188 mitogenic properties, 157 terminomic techniques, 188 serum/plasma, 156 test protease, 188 chain processing, 154–155 COFRADIC. See Combined fractional late endosomes, 150 diagonal chromatography maturation, 153 (COFRADIC) M6P, 149, 150 Collagenolysis non-mammalian species, 151–152 fibril-forming, 440 pH-dependent activation, 155 Hpx domain, 442 phosphotransferase, 149 mammalian collagenases, 441 proteolytic maturation, 150, 151 proteinase action, cartilage collagen fibrils, rodent biosynthesis, 150–151 441, 442 TGN, 149 triple helical structures, 441 Cathepsin L Collagen remodeling, MMPs cDNA, 140 angio-inhibitory fragments, 474 C-terminal epitope tag, 141 type I, 475–476 dimensional structures, 140 type IV, 474–475 disc electrophoretograms, 140 Colon cancer and proteases, 386–387 disulfide bridge, 140, 141 Combined fractional diagonal chromatography high-mannose carbohydrate chains, 142 (COFRADIC) IGF2R, 142 N-termini, 183–184 lysosomal proteases primary amines, 183 and carcinogenesis, 220–221 and SCX, 183 deficient mice, 219 and TNBS, 183 GEM, 219 C-termini isolation, PTMs hair follicles, 219 COFRADIC, 186, 187 keratinocytes, 219 C-TAILS, 186–187 proteolytic activity balance, 218 Cystatin B, 227–228 regular hair growth, 219 Cystatins and stefins, 102 skin barrier function, 221–222 Cysteine cathepsins Index 555

activation and maturation, 135 cysteine cathepsins activity, 131 in cancer, 516 biosynthesis, 147–149 degradative processes at extra- , 148 lysosomal sites, 517 , 147 11 human cysteine cathepsins, 515 , 130–131 as therapeutic targets, 522–523 exopeptidolytic potential, 131 deubiquitinating enzymes or DUBs, 515 products, 136 IGF2R, 148 lysosomal cysteine proteinases, 131 D macrophages, 148 DARP. See Designed ankyrin repeat protein octapeptide, 148 (DARP) model, 131 DDP4. See IV (DDP4) structures Death domains (DD), 279 ERFNIN, 132 Death inducing signaling complex (DISC) , 135 caspase-8, 280 human procathepsin L, 132, 133 DDs, 279 occluding loop, 133, 134 FADD, 279–280 procathepsin B, 133, 134 Degradomics, PTMs procathepsin F, 133 , 180 procathepsin X, 132, 134 C-termini isolation, 186–187 proteolytic activity, 132 MS, 178, 179 Cysteine peptidases, 25 negative selection techniques, 179 Cysteine proteases N-termini isolation (see N-termini cathepsin B isolation, PTMs) absence of, 517 peptide identification, 179 Barrett’s esophagus, 516 positive selection techniques, 179 compensation, 517 protein abundance, 178 siRNA and shRNA technologies, PROTOMAP, 187–188 517–518 terminomics, 178 cathepsin C, 520 Designed ankyrin repeat protein (DARP), cathepsin H, 520 291–293 Dipeptidyl peptidase 2 (DP2), 342–343 osteolytic metastases, 521 Dipeptidyl peptidase 8 (DP8) source, 521 human gene localization, 338 , 522 meningioma, 337 physiological function, 338 tumor proliferation and plasma membrane, 338 angiogenesis, 521 Dipeptidyl peptidase 9 (DP9) uveal melanomas, 521 antigen presentation, 339 cathepsins F and W Arg-Gly-Asp cell attachment, 339 large granular lymphocyte cellular compartmentation and leukemia, 522 glycosylation, 340 macrophages, 521 cytosolic monomer, 338 cathepsins L and V cytotoxicity, 339 CDP/Cux transcription factor, 519 fluorogenic activity assay, 339 nuclear cathepsin in thyroid human meningioma, 339 cancers, 520 post- dipeptidyl aminopeptidase procathepsin L, 519 activity, 339 cathepsin X P2-pocket, 340 deficiencies in both cathepsins rodent brain, 339 X and B, 518 Dipeptidyl peptidase IV (DDP4), 383–384 Helicobacter pylori infection, 519 Dipetidyl peptidase (DP)-like proteins, 340 556 Index

DISC. See Death inducing signaling complex PCP (see Prolylcarboxypeptidase (PCP)) (DISC) FAP. See Fibroblast activation protein alpha DP2. See Dipeptidyl peptidase 2 (DP2) (FAP) DP8. See Dipeptidyl peptidase 8 (DP8) Fas-associated death domain (FADD), 279 DP9. See Dipeptidyl peptidase 9 (DP9) Fetuin, 246, 252, 423 DP4 gene family S9B Fibroblast activation protein alpha (FAP) ADA/CD45, 336 DP4/FAP, 337–338 DP8, 338 Glu203–Glu204, 337 DP9, 338–340 pharmaceutical target, 338 DP-like proteins 1, 340 plasma membrane, 336 Ex-DP4-like enzymes, 340 sequence identity, 337 FAP, 337–338 FLICE-inhibitory protein (FLIP), 290–291 HPA and BBB, 337 FLIP. See FLICE-inhibitory protein (FLIP) human crystal structure, 335 neuropeptides, 336 NPY, 335 post-proline-dipeptidyl peptidase, 335 G Gastrointestinal-tract-specific calpains E activity and substrates β β ECM. See Extracellular matrix (ECM) coatomer complex, -subunit ( -COP), EGF. See Epidermal growth factor (EGF) 412 Endoplasmic reticulum (ER), 128 human calpains, 412 Enzyme inactivation biological significance acetylcholinesterase, 80 ethanol-induced gastric ulcers, 413 low molecular mass compounds, 79 gastric mucosal defense, 413 mechanisms, 76–77 G-calpain, 413 one-step inactivation mechanism, 79 discovery and nomenclature parameters expressions, 78 CAPN8, 410 progress curves and λ dependency, 78 goblet cells in intestines, 410 Epidermal growth factor (EGF), 220 structural features ER. See Endoplasmic reticulum (ER) CAPN2/mCL and CAPN9/nCL-4 as μ Ex-DP4-like enzymes, 340 well as CAPN1/ CL, 411, 420 Exopeptidases, 3–4 3D structures of CysPc domains, 411 Exosites, 3, 285, 327, 439 homo-oligomers, 411 Extracellular forms, cathepsin B GEM. See Genetically engineered mice (GEM) exocytosis, 139–140 General modifier mechanism macromolecules, 139 consistent nomenclature, 56 plasma membrane, 139 individual rate constants, 55 thyroid epithelial cells, 140 non-essential activation, 54 tumour cells, 139 steady-state rate equation, 54–55 Extracellular matrix (ECM) Genetically engineered mice (GEM) blood vessels, 471 cathepsin mouse genetics, 218 macromolecules, 433 cysteine cathepsins, 218 molecules and influence substrate, 434 genome modification, 217 proteinases, 443 human cathepsin L, 219 proteins, 474, 475 skin and hair homeostasis, 222 synthesis and degradation, 471, 481 systematic phenotyping, 217–218 Extrinsic apoptotic pathway, 268 Glutamic peptidases, 26 GraphPad Software, 38

F FADD. See Fas-associated death domain H (FADD) hTERT. See Human telomerase reverse Family S28 transcriptase (hTERT) DP2, 342–343 Human kallikrein (hK) 3, 507 Index 557

Human telomerase reverse transcriptase J (hTERT), 285 Jejunum proteases, 379 Hypothalamic-pituitary adrenal (HPA) axis, 337 K Kallikrein, 190–196, 250, 341, 507–509 Kazal-type inhibitors, 195 I kcat, 39, 40, 47 IBD. See Inflammatory bowel diseases (IBD) Kinetic data analysis IDE. See Insulin-degrading enzyme (IDE) description, 41 IGFBP3. See Insulin growth factor binding enzyme stability, assays, 42–43 proteins (IGFBP3) graphical methods, 43–44 IGF2R. See Insulin-like growth factor II KinTek, 46–47 receptor (IGF2R) non-linear regression, 46 Ileum proteases, 380 regression analysis, 44–45 Inflammasome Simulink, 46 CARD, 281 KinTek, 46–47 NLRP, 280–281 Kunitz-type inhibitors, 383 PIDD, 281–283 pro-caspase-1, 281 L Inflammatory bowel diseases (IBD), 385–386 Large intestine proteases, 381–382 Inflammatory intestinal diseases and proteases, LC. See Liquid-chromatography (LC) 385–386 Liquid-chromatography (LC), 177, 186, 189, Inhibition constant, 59–60, 64, 80 191 Insulin-degrading enzyme (IDE), 97, 329 Lysosomal proteases Insulin growth factor binding proteins cardiovascular system, 222–225 (IGFBP3), 249 cathepsin mouse genetics, 218 Insulin-like growth factor II receptor GEM, 217 (IGF2R), 142 genome modification, 217–218 Integrated rate equations hair cycling, cathepsin L (see Cathepsin L, aldehyde hydrate and cyclic lysosomal proteases) carbinolamine, 68 neurodegenerative disorders, cathepsins, EI complex, 67 225–228 enzyme properties, 71 proteolytic balance, 218 parameters expressions, 68–69 Lysosomal proteinase progress curves, 68 cysteine proteinases, 137, 138 slow-binding inhibition systems, 66–67 gene disruption, 138 temporary inhibition mechanisms, 69, 70 human and rodent cells, 137 Intestinal pathobiology mammalian cells, 137 colon cancer and proteases, 386–387 proteolytic maturation, 137, 138 DDP4 and diabetes, 383–384 inflammatory intestinal diseases and proteases, 385–386 M physiological condition, 382–383 Major excreted polypeptide (MEP), 144 tissue remodeling and wound repair, 384 MALDI. See Matrix-associated laser Isobaric tag for relative and absolute desorption ionization (MALDI) quantification (iTRAQ) Mammalian digestive system Escherichia coli, 182 bacteria, intestine, 373 in silico analysis, 181–182 description, 373 lysine guanidation, 181 duodenum/pancreas proteases, 378–379 MS/MS analysis, 181 functions, protease, 374 N-termini, 181, 182 ileum proteases, 380 iTRAQ. See Isobaric tag for relative and intestinal pathobiology (see Intestinal absolute quantification (iTRAQ) pathobiology) 558 Index

Mammalian digestive system (cont.) invasion, 498–499 jejunum proteases, 379 mammary carcinogenesis, 495–496 large intestine, 381–382 multistage carcinogenesis, 494 proteases, esophagus, 375–376 “sheddase” function of MMPs, 496 salivary proteases, 374–375 tumor initiation and/or promotion, 493 stomach proteases (see Stomach proteases) cartilage matrix-degrading Mannose 6-phosphate (M6P) metalloproteinases, 434, 435 cathepsin B, 130 collagenolytic activities CD63, 146, 147 effects, vessel function and maturation, colocalization, 146 472, 473 endosomal acidification, 129 and TIMPs, 473 and ER, 128 collagen remodeling, 474–476 glycoproteins, 128 C-terminal domain, 456 and IGF2R, 129, 130 and ECM, 433, 471–472 lysosomal enzyme, 130 endothelial cell-cell contact molecules mammalian cells, 129 ADAM-10 effect, 477 mouse fibroblasts, 141, 145–146 diabetic retinopathy, 477 multivesicular endosomes, 146, 147 tight junction proteins, 477 murine fibroblasts, 129 and TJPs, 476 and PA domain, 146–147 family phosphotransferase, 128 collagenases, 493 procathepsin L, 146 MMP-1/collagenase-1, 493 proteolytic maturation, 130 steps in tumor development, 493 and TGN, 145 substrate or inhibitor binding, 492 Mass spectrometry (MS) and inflammation and ABP, 191 chemokine gradients, 498 and LC, 177, 186, 189, 191 melanoma development, 498 N-termini, 182 in metastasis protein turnover, 201, 202 gelatinase MMP-9, 500 PTMs, 177 MMTV-polyoma middle T model, 499 terminal peptides, 178, 179 tumor-associated MMP-9 activity, 530 and TEV, 180 and metzincins (see Metzincins) Matrix-associated laser desorption ionization physiology and vessel function (MALDI), 177 in vivo, 480 Matrix metalloproteinase 2 (MMP-2), 329 Mt1-mmp mice, 479 Matrix metalloproteinases (MMPs) spatial and temporal MT1-MMP ADAMs (see A disintegrin and expression, 479 metalloprotease (ADAMs)) plasma proteinase inhibitor, 455 ADAMTSs and aggrecanases (see and PPS, 458 ADAMTSs) RA and OA, 433, 458 aggrecanases, 434 therapeutic potentials, 481–482 and angiogenesis TIMPs, 456–457 anti-angiogenic properties of tumor progression stages, 494 MMPs, 497 vessel maturation endothelial cell invasion and pericytes, 477–478 migration, 496 TGFβ, 478 Myeloid-Derived Suppressor Cells Membrane-anchored serine proteases (MDSCs), 497 catalytic domain, 509 reduced target, 529 GPI-anchored proteases: prostasin antibodies and allosteric inhibition, 459 E-cadherin expression, 511 in cancer ENaC processing, 511 colorectal cancer, 495 hormone-refractory human prostate gelatin zymography, 493 cancers, 510 genetic ablation of MMP-8 GPI-anchored proteases: testisin (collagenase-2), 495 ovarian carcinoma, 509–510 Index 559

siRNA–mediated knockdown, 510 MMPs. See Matrix metalloproteinases (MMPs) SKOV3, 510 M6P. See Mannose 6-phosphate (M6P) hepsin/TMPRSS1 over-expression, 511–512 in prostate cancer, 512 N regulation of proteolytic activity, 509 N-chemical labeling of the alpha-amine of S1 peptidase family, 509 proteins (N-CLAP) TMPRSS2 and PITC, 182 ETS transcription factors, 514 proteolytic cleavage, 183 TMPRSS2-ETS fusion proteins, 514 and trifluoracetic acid (TFA), 182 TTSPs: matriptase NC-IUBMB. See Nomenclature Committee of carcinogenesis, stages, 512, 513 the International Union of c-Met-mTOR signaling pathway, 513 Biochemistry and Molecular De novo expression, 512 Biology (NC-IUBMB) endogenous matriptase synthesis, 512 NCL. See Neuronal ceroid lipofuscinosis type II serine proteases (TTSPs), 511, 529 (NCL) MEP. See Major excreted polypeptide (MEP) N-CLAP. See N-chemical labeling of the Meprin alpha-amine of proteins (N-CLAP) amyloid precursor protein, 251 NEP. See Neprilysin (NEP) interleukins, 250 Neprilysin (NEP), 328–329 MAM domain, 249–250 Neurodegenerative disorders, cathepsins proteomics approaches, 250 cathepsins B and L, 225 MEROPS cystatin B, neuronal proteolytic balance, families, 7 228–229 identifiers, 9, 23 human cathepsin L homologue (hCTSL), PA, PB and PC, 8 225, 226 proteolytic enzymes, clans and families, neuronal macroautophagy, 227 9–22 neuronal storage disorders, 225–226 Metallopeptidases proteolytic activity, 225, 226 catalytic mechanisms, 26–27 Neuronal ceroid lipofuscinosis (NCL), 225 clan MG Neuronal macroautophagy, 227 active site, 343 Neuronal storage disorders description, 343 axons, 226 prolidase, 346–347 cathepsin B and L, 226 x-prolyl (see X-prolyl cathepsin D deficient mice, 225 aminopeptidases) NCL, 225 clan MH, 347–348 Nomenclature Committee of the International Metzincins Union of Biochemistry and aggrecanase, 436, 437 Molecular Biology (NC-IUBMB), in arthritis, 443–444 271–272 catalytic M domain, 434 Non-linear regression analysis collagenolysis, 440–443 kinetic parameters, 49, 50 crystal structures, 437 Michaelis-Menten equation, 49–50 domain arrangement, 435, 436 SE/SD, 49 3D structures Non-lysosomal localization fibronectin type II domain, 439–440 cell culture medium, 145 Hpx domain, 440 enzyme activity, 143–144 linker region, 440 fibroblasts, 141, 144 M domain, 438–439 intra and extracellular sites, 143 pro-domains, 438 lysosomal cysteine proteases, 144 ribbon structure, 438, 439 MEP, 144 “matrixins”, 434 M6P receptors, 144 pro-enzymes, 435 tumour cells, 145 Michaelis constant (Km), 39, 41 Non-mammalian species 560 Index

Non-mammalian species (cont.) description, 2 Aedes aegypti, 152 exopeptidases, 3–4 affinity chromatography, 151, 152 isopeptide bonds, 5 Caenorhabditis elegans, 152 MEROPS (see MEROPS) cDNA, 151, 152 molecule, 3 Dictyostelium discoideum, 153 omega-peptidases, 5–6 molecular weight, 152 structure, 3, 4 Xenopus laevis, 152 Peptidases interaction Non-productive binding and substrate aspartic and metallopeptidases, 38, 40 inhibition description, 38, 39 description, 61–62 double enzyme-modifier interactions, 81 linear competitive, 63, 65 enzyme inactivation, 76–80 parameters, 62–63 , 37 peptidases, 61 enzyme modification uncompetitive substrate inhibition, 63 classification, 54 N-termini isolation, PTMs general modifier mechanism, 54–56 biotinylation inhibitor complex, 52 N-CLAP, 182–183 non-essential activation, 54 post lysine guanidation, 180–181 non-productive binding and substrate subtiligase, 180, 181 inhibition, 61–64 COFRADIC, 183–184 reversible inhibitors, 53–54 iTRAQ reagents, 181–182 specific velocity plot, 56–59 PTAG, 184 tight-binding inhibition, 59–61 TAILS, 184–185 GraphPad Software, 38 IC50,81 O ‘invisible’ kinetic parameters, 80 OA. See Osteoarthritis (OA) kcat and Km calculation OLETF. See Otsuka Long-Evans Tokushima description, 47 Fatty (OLETF) differential equation, 52 Oligopeptidase, 5 first-order kinetics, 50–51 Omega-peptidases, 5–6 graphical analysis, 47–48 Osteoarthritis (OA) integrated michaelis-menten equation, ADAMTS4 and ADAMTS5, 449 51–52 chondrocytes, 455 non-linear regression analysis, 49–50 ECM-degrading proteinases, 443 kinetic constants, 40–41 and RA, 433, 434, 458 kinetic data analysis, 41–47 Otsuka Long-Evans Tokushima Fatty kinetic notation, 40, 41 (OLETF), 415 kinetic tools, 37 Ovastacin, 237–238, 246, 251 peptidolytic reaction, 40, 41 , 3, 9, 25, 135, 278 reaction mechanism, 38 serine, threonine and cysteine, 38, 40 serpin inhibition mechanism, 74–76 P slow-binding inhibition (see Slow-binding PA. See Protease-associated (PA) inhibition) PARP. See Poly(ADP-Ribose) polymerase symbols, enzyme kinetics, 38, 39 (PARP) Phenyl isothiocyanate (PITC), 182 PCP. See Prolylcarboxypeptidase (PCP) Phospho tagging (PTAG), 184 PCs. See Proprotein convertases (PCs) PICS. See Proteomic identification of protease Pentosan polysulfate (PPS), 458 cleavage sites (PICS) Peptidase p53-induced protein with a death domain and substrate residue (PIDD) nomenclature, 3, 4 autoproteolysis, 282 catalytic type RAIDD, 283 hydrolysis, 5 sequential cleavage, 281–283 pH optimum, 6 ZU-5 domains, 281 Index 561

PITC. See Phenyl isothiocyanate (PITC) Proteases Poly(ADP-Ribose) polymerase (PARP), 285 in AD (see Alzheimer’s disease (AD)) Posttranslational modifications (PTMs) caspases (see Caspases) ABPs, 178 cell deletion, tissues, 266 cell machinery, 176 death pathways cleavage sites, 188–191 anoikis, 270 in vivo, 203, 204 autophagy, 270 interactions cornification, 270 amino acids, 196, 197 entosis, 270 amyloid β-peptide, 199, 200 extrinsic apoptotic pathway, 268 caspase , 199 intrinsic apoptosis, 268–269 cellular homeostasis, 200, 201 mitotic catastrophe, 270 cytosol, 197 necrosis, 269 degradation pathways, 196 netosis, 270 fibrils formation, 199, 200 nomenclature, 267 glycoproteins, 200 parthanatos, 270 Huntington’s disease (HD), 198 pyroptosis, 269 in vitro, 198 extracellular space, 97 phosphorylation, 198–199 and inhibitors proteosomal degradation, 196, 197 cystatins and stefins, 102 SUMO proteins, 198 endo-lysosomal enzymes, 101 UPS, 196, 197 proteolytic activation, 102–103 irreversible nature, 176 invadopodia, 98 MALDI, 177 mammalian digestive system MMP, 177 (see Mammalian digestive system) MS, 177 plasma membrane, 97 N and C terminal degradomics proline-specific peptidases (see Proline- (see Degradomics, PTMs) specific peptidases) pathophysiological processes, 175 Proteasome, see threonine peptidases protease web, 177 Protein topography and migration platform protein turnover, 201–203 (PROTOMAP), 187–188 proteolysis regulation networks (see Protein turnover, PTMs Proteolysis regulation networks) autophagosomal-lysosomal system, 203 PPS. See Pentosan polysulfate (PPS) macroautophagy, 201–202 Prolidase, 346–347 MS based proteomics, 201, 202 Prolinase, 347–348 proteasomal degradation, 201 Proline-specific peptidases UPS, 202 metallopeptidases (see Metallopeptidases) xenophagy, 201 SC/metallopeptidases, 331 Proteolysis serine (see Serine peptidases) amino acids, 104 X-Pro dipeptides, 331 calpains, 105 Prolylcarboxypeptidase (PCP), 341–342 cathepsins, mammalian cells, 88, 91 Prolyl oligopeptidase family S9 cellular organelles, 85, 87 description, 331 compartmentalization principles, 88, 90 DP4 gene family S9B (see DP4 gene cytoplasm, 104 family S9B) environment PEP gene family S9A, 334–335 calpain activity, 88 peptidases and homologues, 334 chromatin, 93 Proprotein convertases (PCs), 95 eukaryotic cells, 94 Prostate-specific antigen (PSA). See Human RIP, 89 kallikrein (hK) 3 enzymes Protease-associated (PA), 146–147 cytoplasm, 103 Protease activated receptor, 376, 383 plasminogen activators, 102–103 562 Index

proteasomes, 103 integral membrane peptidases, 28–29 uPA, 102 and , 30 eu-and prokaryotic cells, 107 peptidase (see Peptidase) extra-and intracellular level, 85, 86 self-cleaving proteins, 29–30 lipid membranes, 88, 89 Proteolytic processing, cathepsin L processing asparaginyl , 143 de novo protein biosynthesis, 95 cathepsin D, 143 endocytic pathway, 96 cysteine proteinases, 137, 143 eukaryotic cells, 96–97 fibroblasts, 141–143 IDE, 97 in vitro and in vivo, 143 mitosis, 94 pulse-chase analysis, 142 PCs, 95 Proteomic identification of protease cleavage secretory pathway, 95 sites (PICS), 189–190 TGN, 95–96 PROTOMAP. See Protein topography and in protein, 87 migration platform (PROTOMAP) proteolytic processing, 94–97 PTAG. See Phospho tagging (PTAG) radical decision-making processes, 98–100 PTMs. See Posttranslational modifications tissues and cell types, 85–86 (PTMs) ubiquitin, 106 Pyroptosis, 269 Proteolysis regulation networks cathepsins B and Z, 193, 194 coagulation factors, 192, 193 R cystatin C and M, 193 RA. See Rheumatoid arthritis (RA) cysteine cathepsins, 192, 193 Radical decision-making processes homeostasis, 192 and degradation, 100 in vitro, 194 endocytic compartments, 99 legumain, 194 endocytic pathway, 99 LEKTI, 195 pH optimum, 100 matriptase, 195 proteases, 98–99 MMP-2, 195 Regulated intramembrane proteolysis (RIP), 89 physiological processes, 192 Rheumatoid arthritis (RA) recombinant protein, 195 aggrecanases, 450 TIMPs, 194, 195 cellular sources, 443 transcriptome analysis, 194 synovial fluids, 456 tumor cell lines, 193, 194 therapeutics, 458 zymogen activation, 192 Rho-associated kinase I (ROCK I) Proteolytic enzymes cardiomyocytes, 288 capsid proteins, 31 phosphorylation targets, 287 catalytic mechanisms signaling pathway, 287–288 aspartic peptidases, 25–26 Rhomboid, 21, 29, 454 cysteine peptidases, 25 RIP. See Regulated intramembrane glutamic peptidases, 26 proteolysis (RIP) metallopeptidases, 26–27 ROCK I. See Rho-associated kinase I (ROCK I) molecule, 23 serine peptidases, 24 threonine peptidases, 24–25 S classifications comparisons, 27–28 Salivary proteases, 374–375 counts, 1–2 SCX. See Strong cation exchange (SCX) description, 1 α-Secretase gram-negative bacteria, 31 ADAM10, 320 hedgehog precursor, 31–32 ADAM9 and ADAM15, 320 hormone, 32 APP, 320 , 30 cell adhesion proteins, 321 Index 563

expression, ADAM10, 321 LGMD2A/calpainopathy, 409 phorbol ester PMA, 321 stretch-induced dynamic redistribution β-Secretase of p94, 409 aspartyl protease BACE1, 322 discovery and nomenclature BACE1, 322–323 calpain catalytic subunits, 406 caspases, 325–326 novel calpains, 406 cathepsins, 324–325 proteolytic activity hypomyelination, 323 autolysis, 407 N-glycosylated type I, 322 connectin/titin, 408 problems, BACE1, 323–324 Lp82, 408 transcriptional level, 323 structural features γ-Secretase CAPN3/p94, 406 ε-cleavage site, 327 CBSW and PEF domains, 406 ectodomain shedding, 327 IS2, 406 endoplasmic reticulum, 327 LGMD2A/calpainopathy pathogenic GXGD proteases, 326 mutations, 407 high-resolution structure, 327 NS, 406 integral membrane proteins, 326 Skin barrier function, cathepsin L substrate specificity, 328 cornification process, 221 TMP21, 326–327 cystatin M/E deficient mice, 221 type I membrane proteins, 327 cysteine proteases, 221 Secreted serine proteases GEM findings, 222 in cancer, 506 and hair homeostasis, 222 high tumor-associated PAI-2 proteolytic balance, 222 expression, 506 stratum corneum, 221 plasminogen activation system Slow-binding inhibition PAI-2 expression, 506 advantages and limitations, 64 RIP1-Tag2 model, 507 integrated rate equations (see Integrated transforming growth factor beta rate equations) (TGF-β), 505 kinetic constants and error analysis, 73–74 uPA deficiency on tumor linear competitive, 65 progression, 507 non-linear regression, 74 tissue kallikrein (KLK) peptidases, 65 genetic animal models, 508 tight-binding inhibition, 71 human kallikrein (hK) 3, 507 Small ubiquitin-like modifier (SUMO), 198 mitogenic peptides, IGF1and IGF2, 508 Stomach proteases prostate-specific antigen (PSA), 507 chymosin, 377 tumor-suppressive actions, 508 gastricsin, 377–378 Seminal fluid, 252 pepsin, 376–377 Serine peptidases, 24 Specificity constant (kcat/Km), 39, 47, 325 DP2 (see Dipeptidyl peptidase 2 (DP2)) Strong cation exchange (SCX), 183 subtilisins family S28, 341–343 SUMO. See Small ubiquitin-like modifier prolyl oligopeptidase family S9 (see Prolyl (SUMO) oligopeptidase family S9) trypsin (family S1) Serpin inhibition mechanism acyl-enzyme complex, 75 T description, 74, 75 Terminal amine isotope labeling of substrates plants and viruses, 74–75 (TAILS) progress curves, 76 and APP, 185 Simulink, 46 and MMP-2, 185 Skeletal-muscle-specific calpain N-terminomic approach, 185 biological significance peptides, 184 564 Index

Terminal amine isotope labeling of substrates ZO-1 degradation, 476 (TAILS) (cont.) TNBS. See Trinitrobenzenesulfonyl (TNBS) primary amines, 184 Tobacco etch virus (TEV), 180 TEV. See Tobacco etch virus (TEV) Tolloid, 247, 437 TGN. See trans-Golgi network (TGN) Transforming growth factor β (TGFβ) Threonine peptidases, 24–25 angiogenesis and vessel maturation, 479 Threonine proteases and MT1-MMP, 480 N-terminal amino acid, 524 trans-Golgi network (TGN), 95–96, 149 proteasome in angiogenesis Trinitrobenzenesulfonyl (TNBS), 183 argyrin against proteasome, 526 Trypsin, 24 tumor suppressive protein Von-Hippel Lindau, 526 U proteasome in drug resistance Ubiquitin proteasome system (UPS), 202 autophagy, 527 Urokinase-type plasminogen activator multidrug resistance (MDR)-1, 527 (uPA), 102 proteasome inhibitors in cancer therapy bortezomib, dipeptidyl boronate inhibitor, 528 V marizomib (NPI-0052), 528 Velocity plot proteasome in inflammation activation constants, 58, 60 anti-inflammatory macrophages, 527 allosteric effectors, 57 regulation of transcription factor properties, 56–57 nuclear factor kappa B (NFκB), 526 quasi-equilibrium assumption, 56 proteasome in tumor initiation/promotion statistical methods, 58–59 adenomatous polyposis coli (APC) gene, 524 X ‘knocked-in’ a mutant p27 kip1, 525 X-linked inhibitor of apoptosis protein TGF-β signal transduction pathway, 524 (XIAP) therapeutic proteasome inhibitors, 525 Asp-148, 290 unfolded protein response (UPR), 525 caspase-3 and-7, 290 20S proteasome, 524 RING domain truncations, 290 26S proteasome, 524 X-prolyl aminopeptidases Thrombin, 189, 193, 383, 477 AmpP1, 344 Tight-binding inhibition AmpP2, 344–345 general modifier mechanism, 59 AmpP3, 345–346 human cathepsin titration, 60–61 kinetic analysis, 61 properties, 60 Z residual activity vs. total inhibitor, 60 Zymogen structure and activation mechanism Tissue inhibitors of metalloproteases (TIMPs) activation site, 245 3D structure, 456, 457 ‘aspartate-switch’, 246 epigenetic regulation, 473 astacin pro-segment, 244–245 N-terminal α-amino group, 457 rigidity and stability, 246