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 enzyme ADAM proteases (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 cathepsins, 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 protease 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 proteins, 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 protein 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 enzymes, 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-caspase-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 Calpain-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 calpains, isoforms, 397 Cardiomyopathy calpastatin, 398 ANP, 225 neutral proteinase (CANP) activity, 397 cathepsin 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 Caspases calpain-1, 395 activated initiator, 273–274 calpastatin, 395 active site architecture and substrate CAPN10 homologs recognition, 277–278 GLUT4 vesicle translocation, 415 amino acid, 275 OLETF, 415 apoptosis 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 cathepsin B (see Cathepsin B) XIAP, 290 cathepsin D (see Cathepsin D) Catalytic mechanism, 23–24, 38, 180, 271, cathepsin L (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 aminopeptidase activity, 131 in cancer, 516 biosynthesis, 147–149 degradative processes at extra- cathepsin C, 148 lysosomal sites, 517 cathepsin H, 147 11 human cysteine cathepsins, 515 endopeptidases, 130–131 as therapeutic targets, 522–523 exopeptidolytic potential, 131 deubiquitinating enzymes or DUBs, 515 gene products, 136 IGF2R, 148 lysosomal cysteine