Skip to main content
PMC home page
Protein Science : A Publication of the Protein Society logoLink to Protein Science : A Publication of the Protein Society
. 1998 Apr;7(4):815–836. doi: 10.1002/pro.5560070401

Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes.

A R Khan 1, M N James 1
PMCID: PMC2143990  PMID: 9568890

Abstract

Proteolytic enzymes are synthesized as inactive precursors, or "zymogens," to prevent unwanted protein degradation, and to enable spatial and temporal regulation of proteolytic activity. Upon sorting or appropriate compartmentalization, zymogen conversion to the active enzyme typically involves limited proteolysis and removal of an "activation segment." The sizes of activation segments range from dipeptide units to independently folding domains comprising more than 100 residues. A common form of the activation segment is an N-terminal extension of the mature enzyme, or "prosegment," that sterically blocks the active site, and thereby prevents binding of substrates. In addition to their inhibitory role, prosegments are frequently important for the folding, stability, and/or intracellular sorting of the zymogen. The mechanisms of conversion to active enzymes are diverse in nature, ranging from enzymatic or nonenzymatic cofactors that trigger activation, to a simple change in pH that results in conversion by an autocatalytic mechanism. Recent X-ray crystallographic studies of zymogens and comparisons with their active counterparts have identified the structural changes that accompany conversion. This review will focus upon the structural basis for inhibition by activation segments, as well as the molecular events that lead to the conversion of zymogens to active enzymes.

Full Text

The Full Text of this article is available as a PDF (14.7 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allaire M., Chernaia M. M., Malcolm B. A., James M. N. Picornaviral 3C cysteine proteinases have a fold similar to chymotrypsin-like serine proteinases. Nature. 1994 May 5;369(6475):72–76. doi: 10.1038/369072a0. [DOI] [PubMed] [Google Scholar]
  2. Auer H. E., Glick D. M. Early events of pepsinogen activation. Biochemistry. 1984 Jun 5;23(12):2735–2739. doi: 10.1021/bi00307a031. [DOI] [PubMed] [Google Scholar]
  3. Avilés F. X., Vendrell J., Guasch A., Coll M., Huber R. Advances in metallo-procarboxypeptidases. Emerging details on the inhibition mechanism and on the activation process. Eur J Biochem. 1993 Feb 1;211(3):381–389. doi: 10.1111/j.1432-1033.1993.tb17561.x. [DOI] [PubMed] [Google Scholar]
  4. Baker D., Shiau A. K., Agard D. A. The role of pro regions in protein folding. Curr Opin Cell Biol. 1993 Dec;5(6):966–970. doi: 10.1016/0955-0674(93)90078-5. [DOI] [PubMed] [Google Scholar]
  5. Baker D., Sohl J. L., Agard D. A. A protein-folding reaction under kinetic control. Nature. 1992 Mar 19;356(6366):263–265. doi: 10.1038/356263a0. [DOI] [PubMed] [Google Scholar]
  6. Bartunik H. D., Summers L. J., Bartsch H. H. Crystal structure of bovine beta-trypsin at 1.5 A resolution in a crystal form with low molecular packing density. Active site geometry, ion pairs and solvent structure. J Mol Biol. 1989 Dec 20;210(4):813–828. doi: 10.1016/0022-2836(89)90110-1. [DOI] [PubMed] [Google Scholar]
  7. Becker J. W., Marcy A. I., Rokosz L. L., Axel M. G., Burbaum J. J., Fitzgerald P. M., Cameron P. M., Esser C. K., Hagmann W. K., Hermes J. D. Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Protein Sci. 1995 Oct;4(10):1966–1976. doi: 10.1002/pro.5560041002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Berti P. J., Storer A. C. Alignment/phylogeny of the papain superfamily of cysteine proteases. J Mol Biol. 1995 Feb 17;246(2):273–283. doi: 10.1006/jmbi.1994.0083. [DOI] [PubMed] [Google Scholar]
  9. Blevins R. A., Tulinsky A. The refinement and the structure of the dimer of alpha-chymotrypsin at 1.67-A resolution. J Biol Chem. 1985 Apr 10;260(7):4264–4275. doi: 10.2210/pdb5cha/pdb. [DOI] [PubMed] [Google Scholar]
  10. Blundell T. L., Johnson M. S. Catching a common fold. Protein Sci. 1993 Jun;2(6):877–883. doi: 10.1002/pro.5560020602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bode W., Engh R., Musil D., Thiele U., Huber R., Karshikov A., Brzin J., Kos J., Turk V. The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases. EMBO J. 1988 Aug;7(8):2593–2599. doi: 10.1002/j.1460-2075.1988.tb03109.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Bode W., Huber R. Crystal structure analysis and refinement of two variants of trigonal trypsinogen: trigonal trypsin and PEG (polyethylene glycol) trypsinogen and their comparison with orthorhombic trypsin and trigonal trypsinogen. FEBS Lett. 1978 Jun 15;90(2):265–269. doi: 10.1016/0014-5793(78)80382-2. [DOI] [PubMed] [Google Scholar]
  13. Bode W., Huber R. Natural protein proteinase inhibitors and their interaction with proteinases. Eur J Biochem. 1992 Mar 1;204(2):433–451. doi: 10.1111/j.1432-1033.1992.tb16654.x. [DOI] [PubMed] [Google Scholar]
  14. Bode W., Renatus M. Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function. Curr Opin Struct Biol. 1997 Dec;7(6):865–872. doi: 10.1016/s0959-440x(97)80159-5. [DOI] [PubMed] [Google Scholar]
  15. Bode W., Schwager P., Huber R. The transition of bovine trypsinogen to a trypsin-like state upon strong ligand binding. The refined crystal structures of the bovine trypsinogen-pancreatic trypsin inhibitor complex and of its ternary complex with Ile-Val at 1.9 A resolution. J Mol Biol. 1978 Jan 5;118(1):99–112. doi: 10.1016/0022-2836(78)90246-2. [DOI] [PubMed] [Google Scholar]
  16. Bode W., Schwager P. The refined crystal structure of bovine beta-trypsin at 1.8 A resolution. II. Crystallographic refinement, calcium binding site, benzamidine binding site and active site at pH 7.0. J Mol Biol. 1975 Nov 15;98(4):693–717. doi: 10.1016/s0022-2836(75)80005-2. [DOI] [PubMed] [Google Scholar]
  17. Bode W. The transition of bovine trypsinogen to a trypsin-like state upon strong ligand binding. II. The binding of the pancreatic trypsin inhibitor and of isoleucine-valine and of sequentially related peptides to trypsinogen and to p-guanidinobenzoate-trypsinogen. J Mol Biol. 1979 Feb 5;127(4):357–374. doi: 10.1016/0022-2836(79)90227-4. [DOI] [PubMed] [Google Scholar]
  18. Bolognesi M., Gatti G., Menagatti E., Guarneri M., Marquart M., Papamokos E., Huber R. Three-dimensional structure of the complex between pancreatic secretory trypsin inhibitor (Kazal type) and trypsinogen at 1.8 A resolution. Structure solution, crystallographic refinement and preliminary structural interpretation. J Mol Biol. 1982 Dec 25;162(4):839–868. doi: 10.1016/0022-2836(82)90550-2. [DOI] [PubMed] [Google Scholar]
  19. Bonten E. J., Galjart N. J., Willemsen R., Usmany M., Vlak J. M., d'Azzo A. Lysosomal protective protein/cathepsin A. Role of the "linker" domain in catalytic activation. J Biol Chem. 1995 Nov 3;270(44):26441–26445. doi: 10.1074/jbc.270.44.26441. [DOI] [PubMed] [Google Scholar]
  20. Brannigan J. A., Dodson G., Duggleby H. J., Moody P. C., Smith J. L., Tomchick D. R., Murzin A. G. A protein catalytic framework with an N-terminal nucleophile is capable of self-activation. Nature. 1995 Nov 23;378(6555):416–419. doi: 10.1038/378416a0. [DOI] [PubMed] [Google Scholar]
  21. Brayer G. D., Delbaere L. T., James M. N. Molecular structure of the alpha-lytic protease from Myxobacter 495 at 2.8 Angstroms resolution. J Mol Biol. 1979 Jul 15;131(4):743–775. doi: 10.1016/0022-2836(79)90200-6. [DOI] [PubMed] [Google Scholar]
  22. Brenner S. The molecular evolution of genes and proteins: a tale of two serines. Nature. 1988 Aug 11;334(6182):528–530. doi: 10.1038/334528a0. [DOI] [PubMed] [Google Scholar]
  23. Bryan P., Wang L., Hoskins J., Ruvinov S., Strausberg S., Alexander P., Almog O., Gilliland G., Gallagher T. Catalysis of a protein folding reaction: mechanistic implications of the 2.0 A structure of the subtilisin-prodomain complex. Biochemistry. 1995 Aug 15;34(32):10310–10318. doi: 10.1021/bi00032a026. [DOI] [PubMed] [Google Scholar]
  24. Burgos F. J., Pascual R., Vendrell J., Cuchillo C. M., Avilés F. X. The separation of pancreatic procarboxypeptidases by high-performance liquid chromatography and chromatofocusing. J Chromatogr. 1989 Nov 3;481:233–243. doi: 10.1016/s0021-9673(01)96767-6. [DOI] [PubMed] [Google Scholar]
  25. Burgos F. J., Salvà M., Villegas V., Soriano F., Mendez E., Avilés F. X. Analysis of the activation process of porcine procarboxypeptidase B and determination of the sequence of its activation segment. Biochemistry. 1991 Apr 23;30(16):4082–4089. doi: 10.1021/bi00230a038. [DOI] [PubMed] [Google Scholar]
  26. Carmona E., Dufour E., Plouffe C., Takebe S., Mason P., Mort J. S., Ménard R. Potency and selectivity of the cathepsin L propeptide as an inhibitor of cysteine proteases. Biochemistry. 1996 Jun 25;35(25):8149–8157. doi: 10.1021/bi952736s. [DOI] [PubMed] [Google Scholar]
  27. Chen P., Hochstrasser M. Autocatalytic subunit processing couples active site formation in the 20S proteasome to completion of assembly. Cell. 1996 Sep 20;86(6):961–972. doi: 10.1016/s0092-8674(00)80171-3. [DOI] [PubMed] [Google Scholar]
  28. Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13–21. doi: 10.1016/0092-8674(94)90396-4. [DOI] [PubMed] [Google Scholar]
  29. Cohen G. H., Silverton E. W., Davies D. R. Refined crystal structure of gamma-chymotrypsin at 1.9 A resolution. Comparison with other pancreatic serine proteases. J Mol Biol. 1981 Jun 5;148(4):449–479. doi: 10.1016/0022-2836(81)90186-8. [DOI] [PubMed] [Google Scholar]
  30. Coulombe R., Grochulski P., Sivaraman J., Ménard R., Mort J. S., Cygler M. Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment. EMBO J. 1996 Oct 15;15(20):5492–5503. [PMC free article] [PubMed] [Google Scholar]
  31. Cutfield S. M., Dodson E. J., Anderson B. F., Moody P. C., Marshall C. J., Sullivan P. A., Cutfield J. F. The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors. Structure. 1995 Nov 15;3(11):1261–1271. doi: 10.1016/s0969-2126(01)00261-1. [DOI] [PubMed] [Google Scholar]
  32. Cygler M., Sivaraman J., Grochulski P., Coulombe R., Storer A. C., Mort J. S. Structure of rat procathepsin B: model for inhibition of cysteine protease activity by the proregion. Structure. 1996 Apr 15;4(4):405–416. doi: 10.1016/s0969-2126(96)00046-9. [DOI] [PubMed] [Google Scholar]
  33. D'Azzo A., Hoogeveen A., Reuser A. J., Robinson D., Galjaard H. Molecular defect in combined beta-galactosidase and neuraminidase deficiency in man. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4535–4539. doi: 10.1073/pnas.79.15.4535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. DAVIE E. W., NEURATH H. Identification of a peptide released during autocatalytic activation of trypsinogen. J Biol Chem. 1955 Feb;212(2):515–529. [PubMed] [Google Scholar]
  35. Davie E. W., Fujikawa K., Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 1991 Oct 29;30(43):10363–10370. doi: 10.1021/bi00107a001. [DOI] [PubMed] [Google Scholar]
  36. Davies D. R. The structure and function of the aspartic proteinases. Annu Rev Biophys Biophys Chem. 1990;19:189–215. doi: 10.1146/annurev.bb.19.060190.001201. [DOI] [PubMed] [Google Scholar]
  37. Docherty A. J., O'Connell J., Crabbe T., Angal S., Murphy G. The matrix metalloproteinases and their natural inhibitors: prospects for treating degenerative tissue diseases. Trends Biotechnol. 1992 Jun;10(6):200–207. doi: 10.1016/0167-7799(92)90214-g. [DOI] [PubMed] [Google Scholar]
  38. Dunn B. Splitting image. Nat Struct Biol. 1997 Dec;4(12):969–972. doi: 10.1038/nsb1297-969. [DOI] [PubMed] [Google Scholar]
  39. Endrizzi J. A., Breddam K., Remington S. J. 2.8-A structure of yeast serine carboxypeptidase. Biochemistry. 1994 Sep 20;33(37):11106–11120. doi: 10.1021/bi00203a007. [DOI] [PubMed] [Google Scholar]
  40. Fehlhammer H., Bode W., Huber R. Crystal structure of bovine trypsinogen at 1-8 A resolution. II. Crystallographic refinement, refined crystal structure and comparison with bovine trypsin. J Mol Biol. 1977 Apr 25;111(4):415–438. doi: 10.1016/s0022-2836(77)80062-4. [DOI] [PubMed] [Google Scholar]
  41. Foltmann B., Jensen A. L. Human progastricsin. Analysis of intermediates during activation into gastricsin and determination of the amino acid sequence of the propart. Eur J Biochem. 1982 Nov;128(1):63–70. [PubMed] [Google Scholar]
  42. Francis S. E., Banerjee R., Goldberg D. E. Biosynthesis and maturation of the malaria aspartic hemoglobinases plasmepsins I and II. J Biol Chem. 1997 Jun 6;272(23):14961–14968. doi: 10.1074/jbc.272.23.14961. [DOI] [PubMed] [Google Scholar]
  43. Freer S. T., Kraut J., Robertus J. D., Wright H. T., Xuong N. H. Chymotrypsinogen: 2.5-angstrom crystal structure, comparison with alpha-chymotrypsin, and implications for zymogen activation. Biochemistry. 1970 Apr 28;9(9):1997–2009. doi: 10.1021/bi00811a022. [DOI] [PubMed] [Google Scholar]
  44. Galjart N. J., Morreau H., Willemsen R., Gillemans N., Bonten E. J., d'Azzo A. Human lysosomal protective protein has cathepsin A-like activity distinct from its protective function. J Biol Chem. 1991 Aug 5;266(22):14754–14762. [PubMed] [Google Scholar]
  45. Gallagher T., Gilliland G., Wang L., Bryan P. The prosegment-subtilisin BPN' complex: crystal structure of a specific 'foldase'. Structure. 1995 Sep 15;3(9):907–914. doi: 10.1016/S0969-2126(01)00225-8. [DOI] [PubMed] [Google Scholar]
  46. Glick D. M., Shalitin Y., Hilt C. R. Studies on the irreversible step of pepsinogen activation. Biochemistry. 1989 Mar 21;28(6):2626–2630. doi: 10.1021/bi00432a040. [DOI] [PubMed] [Google Scholar]
  47. Gomis-Rüth F. X., Gómez-Ortiz M., Vendrell J., Ventura S., Bode W., Huber R., Avilés F. X. Crystal structure of an oligomer of proteolytic zymogens: detailed conformational analysis of the bovine ternary complex and implications for their activation. J Mol Biol. 1997 Jun 27;269(5):861–880. doi: 10.1006/jmbi.1997.1040. [DOI] [PubMed] [Google Scholar]
  48. Greenberg A. H. Granzyme B-induced apoptosis. Adv Exp Med Biol. 1996;406:219–228. doi: 10.1007/978-1-4899-0274-0_23. [DOI] [PubMed] [Google Scholar]
  49. Groettrup M., Soza A., Kuckelkorn U., Kloetzel P. M. Peptide antigen production by the proteasome: complexity provides efficiency. Immunol Today. 1996 Sep;17(9):429–435. doi: 10.1016/0167-5699(96)10051-7. [DOI] [PubMed] [Google Scholar]
  50. Groll M., Ditzel L., Löwe J., Stock D., Bochtler M., Bartunik H. D., Huber R. Structure of 20S proteasome from yeast at 2.4 A resolution. Nature. 1997 Apr 3;386(6624):463–471. doi: 10.1038/386463a0. [DOI] [PubMed] [Google Scholar]
  51. Hanson J. E., Kaplan A. P., Bartlett P. A. Phosphonate analogues of carboxypeptidase A substrates are potent transition-state analogue inhibitors. Biochemistry. 1989 Jul 25;28(15):6294–6305. doi: 10.1021/bi00441a022. [DOI] [PubMed] [Google Scholar]
  52. Hayano T., Sogawa K., Ichihara Y., Fujii-Kuriyama Y., Takahashi K. Primary structure of human pepsinogen C gene. J Biol Chem. 1988 Jan 25;263(3):1382–1385. [PubMed] [Google Scholar]
  53. Ichihara Y., Sogawa K., Morohashi K., Fujii-Kuriyama Y., Takahashi K. Nucleotide sequence of a nearly full-length cDNA coding for pepsinogen of rat gastric mucosa. Eur J Biochem. 1986 Nov 17;161(1):7–12. doi: 10.1111/j.1432-1033.1986.tb10117.x. [DOI] [PubMed] [Google Scholar]
  54. Jackman H. L., Morris P. W., Deddish P. A., Skidgel R. A., Erdös E. G. Inactivation of endothelin I by deamidase (lysosomal protective protein). J Biol Chem. 1992 Feb 15;267(5):2872–2875. [PubMed] [Google Scholar]
  55. James M. N., Sielecki A. R., Hayakawa K., Gelb M. H. Crystallographic analysis of transition state mimics bound to penicillopepsin: difluorostatine- and difluorostatone-containing peptides. Biochemistry. 1992 Apr 21;31(15):3872–3886. doi: 10.1021/bi00130a019. [DOI] [PubMed] [Google Scholar]
  56. James M. N., Sielecki A. R. Molecular structure of an aspartic proteinase zymogen, porcine pepsinogen, at 1.8 A resolution. Nature. 1986 Jan 2;319(6048):33–38. doi: 10.1038/319033a0. [DOI] [PubMed] [Google Scholar]
  57. Jia Z., Hasnain S., Hirama T., Lee X., Mort J. S., To R., Huber C. P. Crystal structures of recombinant rat cathepsin B and a cathepsin B-inhibitor complex. Implications for structure-based inhibitor design. J Biol Chem. 1995 Mar 10;270(10):5527–5533. doi: 10.1074/jbc.270.10.5527. [DOI] [PubMed] [Google Scholar]
  58. Kageyama T., Ichinose M., Tsukada S., Miki K., Kurokawa K., Koiwai O., Tanji M., Yakabe E., Athauda S. B., Takahashi K. Gastric procathepsin E and progastricsin from guinea pig. Purification, molecular cloning of cDNAs, and characterization of enzymatic properties, with special reference to procathepsin E. J Biol Chem. 1992 Aug 15;267(23):16450–16459. [PubMed] [Google Scholar]
  59. Kageyama T., Takahashi K. The complete amino acid sequence of monkey pepsinogen A. J Biol Chem. 1986 Apr 5;261(10):4395–4405. [PubMed] [Google Scholar]
  60. Kageyama T., Takahashi K. The complete amino acid sequence of monkey progastricsin. J Biol Chem. 1986 Apr 5;261(10):4406–4419. [PubMed] [Google Scholar]
  61. Kam C. M., McRae B. J., Harper J. W., Niemann M. A., Volanakis J. E., Powers J. C. Human complement proteins D, C2, and B. Active site mapping with peptide thioester substrates. J Biol Chem. 1987 Mar 15;262(8):3444–3451. [PubMed] [Google Scholar]
  62. Kay J., Kassell B. The autoactivation of trypsinogen. J Biol Chem. 1971 Nov;246(21):6661–6665. [PubMed] [Google Scholar]
  63. Kerfelec B., Chapus C., Puigserver A. Existence of ternary complexes of procarboxypeptidase A in the pancreas of some ruminant species. Eur J Biochem. 1985 Sep 16;151(3):515–519. doi: 10.1111/j.1432-1033.1985.tb09132.x. [DOI] [PubMed] [Google Scholar]
  64. Kerr M. A., Walsh K. A., Neurath H. A proposal for the mechanism of chymotrypsinogen activation. Biochemistry. 1976 Dec 14;15(25):5566–5570. doi: 10.1021/bi00670a022. [DOI] [PubMed] [Google Scholar]
  65. Kerr M. A., Walsh K. A., Neurath H. Catalysis by serine proteases and their zymogens. A study of acyl intermediates by circular dichroism. Biochemistry. 1975 Nov 18;14(23):5088–5094. doi: 10.1021/bi00694a010. [DOI] [PubMed] [Google Scholar]
  66. Khan A. R., Cherney M. M., Tarasova N. I., James M. N. Structural characterization of activation 'intermediate 2' on the pathway to human gastricsin. Nat Struct Biol. 1997 Dec;4(12):1010–1015. doi: 10.1038/nsb1297-1010. [DOI] [PubMed] [Google Scholar]
  67. Kim H., Lipscomb W. N. Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography. Biochemistry. 1991 Aug 20;30(33):8171–8180. doi: 10.1021/bi00247a012. [DOI] [PubMed] [Google Scholar]
  68. Kim S., Narayana S. V., Volanakis J. E. Mutational analysis of the substrate binding site of human complement factor D. Biochemistry. 1994 Dec 6;33(48):14393–14399. doi: 10.1021/bi00252a004. [DOI] [PubMed] [Google Scholar]
  69. Klionsky D. J., Banta L. M., Emr S. D. Intracellular sorting and processing of a yeast vacuolar hydrolase: proteinase A propeptide contains vacuolar targeting information. Mol Cell Biol. 1988 May;8(5):2105–2116. doi: 10.1128/mcb.8.5.2105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Koklitis P. A., Murphy G., Sutton C., Angal S. Purification of recombinant human prostromelysin. Studies on heat activation to give high-Mr and low-Mr active forms, and a comparison of recombinant with natural stromelysin activities. Biochem J. 1991 May 15;276(Pt 1):217–221. doi: 10.1042/bj2760217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Kossiakoff A. A., Chambers J. L., Kay L. M., Stroud R. M. Structure of bovine trypsinogen at 1.9 A resolution. Biochemistry. 1977 Feb 22;16(4):654–664. doi: 10.1021/bi00623a016. [DOI] [PubMed] [Google Scholar]
  72. Kraut J. Serine proteases: structure and mechanism of catalysis. Annu Rev Biochem. 1977;46:331–358. doi: 10.1146/annurev.bi.46.070177.001555. [DOI] [PubMed] [Google Scholar]
  73. Lamba D., Bauer M., Huber R., Fischer S., Rudolph R., Kohnert U., Bode W. The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator. J Mol Biol. 1996 Apr 26;258(1):117–135. doi: 10.1006/jmbi.1996.0238. [DOI] [PubMed] [Google Scholar]
  74. Laskowski M., Jr, Kato I. Protein inhibitors of proteinases. Annu Rev Biochem. 1980;49:593–626. doi: 10.1146/annurev.bi.49.070180.003113. [DOI] [PubMed] [Google Scholar]
  75. Liao D. I., Breddam K., Sweet R. M., Bullock T., Remington S. J. Refined atomic model of wheat serine carboxypeptidase II at 2.2-A resolution. Biochemistry. 1992 Oct 13;31(40):9796–9812. doi: 10.1021/bi00155a037. [DOI] [PubMed] [Google Scholar]
  76. Liszewski M. K., Farries T. C., Lublin D. M., Rooney I. A., Atkinson J. P. Control of the complement system. Adv Immunol. 1996;61:201–283. doi: 10.1016/s0065-2776(08)60868-8. [DOI] [PubMed] [Google Scholar]
  77. Madison E. L., Kobe A., Gething M. J., Sambrook J. F., Goldsmith E. J. Converting tissue plasminogen activator to a zymogen: a regulatory triad of Asp-His-Ser. Science. 1993 Oct 15;262(5132):419–421. doi: 10.1126/science.8211162. [DOI] [PubMed] [Google Scholar]
  78. Martzen M. R., McMullen B. A., Smith N. E., Fujikawa K., Peanasky R. J. Primary structure of the major pepsin inhibitor from the intestinal parasitic nematode Ascaris suum. Biochemistry. 1990 Aug 14;29(32):7366–7372. doi: 10.1021/bi00484a003. [DOI] [PubMed] [Google Scholar]
  79. Mason R. W., Massey S. D. Surface activation of pro-cathepsin L. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1659–1666. doi: 10.1016/0006-291x(92)90268-p. [DOI] [PubMed] [Google Scholar]
  80. Matthews D. A., Alden R. A., Birktoft J. J., Freer T., Kraut J. Re-examination of the charge relay system in subtilisin comparison with other serine proteases. J Biol Chem. 1977 Dec 25;252(24):8875–8883. [PubMed] [Google Scholar]
  81. McIntyre G. F., Godbold G. D., Erickson A. H. The pH-dependent membrane association of procathepsin L is mediated by a 9-residue sequence within the propeptide. J Biol Chem. 1994 Jan 7;269(1):567–572. [PubMed] [Google Scholar]
  82. Moore S. A., Sielecki A. R., Chernaia M. M., Tarasova N. I., James M. N. Crystal and molecular structures of human progastricsin at 1.62 A resolution. J Mol Biol. 1995 Mar 31;247(3):466–485. doi: 10.1006/jmbi.1994.0154. [DOI] [PubMed] [Google Scholar]
  83. Morgan P. H., Walsh K. A., Neurath H. Inactivation of trypsinogen by methane sulfonyl fluoride. FEBS Lett. 1974 Apr 15;41(1):108–110. doi: 10.1016/0014-5793(74)80965-8. [DOI] [PubMed] [Google Scholar]
  84. Murphy G. J., Murphy G., Reynolds J. J. The origin of matrix metalloproteinases and their familial relationships. FEBS Lett. 1991 Sep 2;289(1):4–7. doi: 10.1016/0014-5793(91)80895-a. [DOI] [PubMed] [Google Scholar]
  85. Müller-Eberhard H. J. Molecular organization and function of the complement system. Annu Rev Biochem. 1988;57:321–347. doi: 10.1146/annurev.bi.57.070188.001541. [DOI] [PubMed] [Google Scholar]
  86. Nagase H., Enghild J. J., Suzuki K., Salvesen G. Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl)mercuric acetate. Biochemistry. 1990 Jun 19;29(24):5783–5789. doi: 10.1021/bi00476a020. [DOI] [PubMed] [Google Scholar]
  87. Nagase H., Suzuki K., Enghild J. J., Salvesen G. Stepwise activation mechanisms of the precursors of matrix metalloproteinases 1 (tissue collagenase) and 3 (stromelysin). Biomed Biochim Acta. 1991;50(4-6):749–754. [PubMed] [Google Scholar]
  88. Narayana S. V., Carson M., el-Kabbani O., Kilpatrick J. M., Moore D., Chen X., Bugg C. E., Volanakis J. E., DeLucas L. J. Structure of human factor D. A complement system protein at 2.0 A resolution. J Mol Biol. 1994 Jan 14;235(2):695–708. doi: 10.1006/jmbi.1994.1021. [DOI] [PubMed] [Google Scholar]
  89. Navia M. A., Fitzgerald P. M., McKeever B. M., Leu C. T., Heimbach J. C., Herber W. K., Sigal I. S., Darke P. L., Springer J. P. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature. 1989 Feb 16;337(6208):615–620. doi: 10.1038/337615a0. [DOI] [PubMed] [Google Scholar]
  90. Neurath H., Walsh K. A. Role of proteolytic enzymes in biological regulation (a review). Proc Natl Acad Sci U S A. 1976 Nov;73(11):3825–3832. doi: 10.1073/pnas.73.11.3825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Okada Y., Harris E. D., Jr, Nagase H. The precursor of a metalloendopeptidase from human rheumatoid synovial fibroblasts. Purification and mechanisms of activation by endopeptidases and 4-aminophenylmercuric acetate. Biochem J. 1988 Sep 15;254(3):731–741. doi: 10.1042/bj2540731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Okada Y., Nakanishi I. Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 ('gelatinase') by human neutrophil elastase and cathepsin G. FEBS Lett. 1989 Jun 5;249(2):353–356. doi: 10.1016/0014-5793(89)80657-x. [DOI] [PubMed] [Google Scholar]
  93. Ollis D. L., Cheah E., Cygler M., Dijkstra B., Frolow F., Franken S. M., Harel M., Remington S. J., Silman I., Schrag J. The alpha/beta hydrolase fold. Protein Eng. 1992 Apr;5(3):197–211. doi: 10.1093/protein/5.3.197. [DOI] [PubMed] [Google Scholar]
  94. Palmenberg A. C. Proteolytic processing of picornaviral polyprotein. Annu Rev Microbiol. 1990;44:603–623. doi: 10.1146/annurev.mi.44.100190.003131. [DOI] [PubMed] [Google Scholar]
  95. Palmenberg A. C., Rueckert R. R. Evidence for intramolecular self-cleavage of picornaviral replicase precursors. J Virol. 1982 Jan;41(1):244–249. doi: 10.1128/jvi.41.1.244-249.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Palombella V. J., Rando O. J., Goldberg A. L., Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. doi: 10.1016/s0092-8674(94)90482-0. [DOI] [PubMed] [Google Scholar]
  97. Pan D., Rubin G. M. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell. 1997 Jul 25;90(2):271–280. doi: 10.1016/s0092-8674(00)80335-9. [DOI] [PubMed] [Google Scholar]
  98. Pascual R., Vendrell J., Avilés F. X., Bonicel J., Wicker C., Puigserver A. Autolysis of proproteinase E in bovine procarboxypeptidase A ternary complex gives rise to subunit III. FEBS Lett. 1990 Dec 17;277(1-2):37–41. doi: 10.1016/0014-5793(90)80804-r. [DOI] [PubMed] [Google Scholar]
  99. Perona J. J., Craik C. S. Structural basis of substrate specificity in the serine proteases. Protein Sci. 1995 Mar;4(3):337–360. doi: 10.1002/pro.5560040301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Peters J. M. Proteasomes: protein degradation machines of the cell. Trends Biochem Sci. 1994 Sep;19(9):377–382. doi: 10.1016/0968-0004(94)90115-5. [DOI] [PubMed] [Google Scholar]
  101. Pignol D., Granon S., Chapus C., Fontecilla-Camps J. C. Crystallographic study of a cleaved, non-activatable form of porcine zymogen E. J Mol Biol. 1995 Sep 8;252(1):20–24. doi: 10.1006/jmbi.1995.0471. [DOI] [PubMed] [Google Scholar]
  102. Polgár L., Halász P. Current problems in mechanistic studies of serine and cysteine proteinases. Biochem J. 1982 Oct 1;207(1):1–10. doi: 10.1042/bj2070001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Potempa J., Korzus E., Travis J. The serpin superfamily of proteinase inhibitors: structure, function, and regulation. J Biol Chem. 1994 Jun 10;269(23):15957–15960. [PubMed] [Google Scholar]
  104. Rees D. C., Lewis M., Lipscomb W. N. Refined crystal structure of carboxypeptidase A at 1.54 A resolution. J Mol Biol. 1983 Aug 5;168(2):367–387. doi: 10.1016/s0022-2836(83)80024-2. [DOI] [PubMed] [Google Scholar]
  105. Rees D. C., Lipscomb W. N. Refined crystal structure of the potato inhibitor complex of carboxypeptidase A at 2.5 A resolution. J Mol Biol. 1982 Sep 25;160(3):475–498. doi: 10.1016/0022-2836(82)90309-6. [DOI] [PubMed] [Google Scholar]
  106. Reinemer P., Grams F., Huber R., Kleine T., Schnierer S., Piper M., Tschesche H., Bode W. Structural implications for the role of the N terminus in the 'superactivation' of collagenases. A crystallographic study. FEBS Lett. 1994 Jan 31;338(2):227–233. doi: 10.1016/0014-5793(94)80370-6. [DOI] [PubMed] [Google Scholar]
  107. Renatus M., Engh R. A., Stubbs M. T., Huber R., Fischer S., Kohnert U., Bode W. Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA. EMBO J. 1997 Aug 15;16(16):4797–4805. doi: 10.1093/emboj/16.16.4797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Robertus J. D., Kraut J., Alden R. A., Birktoft J. J. Subtilisin; a stereochemical mechanism involving transition-state stabilization. Biochemistry. 1972 Nov 7;11(23):4293–4303. doi: 10.1021/bi00773a016. [DOI] [PubMed] [Google Scholar]
  109. Rudenko G., Bonten E., d'Azzo A., Hol W. G. Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism. Structure. 1995 Nov 15;3(11):1249–1259. doi: 10.1016/s0969-2126(01)00260-x. [DOI] [PubMed] [Google Scholar]
  110. Ryan C. A. Proteinase inhibitor gene families: strategies for transformation to improve plant defenses against herbivores. Bioessays. 1989 Jan;10(1):20–24. doi: 10.1002/bies.950100106. [DOI] [PubMed] [Google Scholar]
  111. Schechter I., Berger A. On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun. 1967 Apr 20;27(2):157–162. doi: 10.1016/s0006-291x(67)80055-x. [DOI] [PubMed] [Google Scholar]
  112. Seemuller E., Lupas A., Baumeister W. Autocatalytic processing of the 20S proteasome. Nature. 1996 Aug 1;382(6590):468–471. doi: 10.1038/382468a0. [DOI] [PubMed] [Google Scholar]
  113. Sielecki A. R., Hayakawa K., Fujinaga M., Murphy M. E., Fraser M., Muir A. K., Carilli C. T., Lewicki J. A., Baxter J. D., James M. N. Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution. Science. 1989 Mar 10;243(4896):1346–1351. doi: 10.1126/science.2493678. [DOI] [PubMed] [Google Scholar]
  114. Sohl J. L., Shiau A. K., Rader S. D., Wilk B. J., Agard D. A. Inhibition of alpha-lytic protease by pro region C-terminal steric occlusion of the active site. Biochemistry. 1997 Apr 1;36(13):3894–3902. doi: 10.1021/bi962341o. [DOI] [PubMed] [Google Scholar]
  115. Sprang S., Standing T., Fletterick R. J., Stroud R. M., Finer-Moore J., Xuong N. H., Hamlin R., Rutter W. J., Craik C. S. The three-dimensional structure of Asn102 mutant of trypsin: role of Asp102 in serine protease catalysis. Science. 1987 Aug 21;237(4817):905–909. doi: 10.1126/science.3112942. [DOI] [PubMed] [Google Scholar]
  116. Stein P. E., Carrell R. W. What do dysfunctional serpins tell us about molecular mobility and disease? Nat Struct Biol. 1995 Feb;2(2):96–113. doi: 10.1038/nsb0295-96. [DOI] [PubMed] [Google Scholar]
  117. Steiner D. F., Smeekens S. P., Ohagi S., Chan S. J. The new enzymology of precursor processing endoproteases. J Biol Chem. 1992 Nov 25;267(33):23435–23438. [PubMed] [Google Scholar]
  118. Steitz T. A., Henderson R., Blow D. M. Structure of crystalline alpha-chymotrypsin. 3. Crystallographic studies of substrates and inhibitors bound to the active site of alpha-chymotrypsin. J Mol Biol. 1969 Dec 14;46(2):337–348. doi: 10.1016/0022-2836(69)90426-4. [DOI] [PubMed] [Google Scholar]
  119. Steitz T. A., Shulman R. G. Crystallographic and NMR studies of the serine proteases. Annu Rev Biophys Bioeng. 1982;11:419–444. doi: 10.1146/annurev.bb.11.060182.002223. [DOI] [PubMed] [Google Scholar]
  120. Storer A. C., Ménard R. Catalytic mechanism in papain family of cysteine peptidases. Methods Enzymol. 1994;244:486–500. doi: 10.1016/0076-6879(94)44035-2. [DOI] [PubMed] [Google Scholar]
  121. Strausberg S., Alexander P., Wang L., Schwarz F., Bryan P. Catalysis of a protein folding reaction: thermodynamic and kinetic analysis of subtilisin BPN' interactions with its propeptide fragment. Biochemistry. 1993 Aug 17;32(32):8112–8119. doi: 10.1021/bi00083a009. [DOI] [PubMed] [Google Scholar]
  122. Taggart R. T., Cass L. G., Mohandas T. K., Derby P., Barr P. J., Pals G., Bell G. I. Human pepsinogen C (progastricsin). Isolation of cDNA clones, localization to chromosome 6, and sequence homology with pepsinogen A. J Biol Chem. 1989 Jan 5;264(1):375–379. [PubMed] [Google Scholar]
  123. Tanford C. How protein chemists learned about the hydrophobic factor. Protein Sci. 1997 Jun;6(6):1358–1366. doi: 10.1002/pro.5560060627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Tang J., James M. N., Hsu I. N., Jenkins J. A., Blundell T. L. Structural evidence for gene duplication in the evolution of the acid proteases. Nature. 1978 Feb 16;271(5646):618–621. doi: 10.1038/271618a0. [DOI] [PubMed] [Google Scholar]
  125. Tao K., Stearns N. A., Dong J., Wu Q. L., Sahagian G. G. The proregion of cathepsin L is required for proper folding, stability, and ER exit. Arch Biochem Biophys. 1994 May 15;311(1):19–27. doi: 10.1006/abbi.1994.1203. [DOI] [PubMed] [Google Scholar]
  126. Tsukada H., Blow D. M. Structure of alpha-chymotrypsin refined at 1.68 A resolution. J Mol Biol. 1985 Aug 20;184(4):703–711. doi: 10.1016/0022-2836(85)90314-6. [DOI] [PubMed] [Google Scholar]
  127. Turk D., Podobnik M., Kuhelj R., Dolinar M., Turk V. Crystal structures of human procathepsin B at 3.2 and 3.3 Angstroms resolution reveal an interaction motif between a papain-like cysteine protease and its propeptide. FEBS Lett. 1996 Apr 22;384(3):211–214. doi: 10.1016/0014-5793(96)00309-2. [DOI] [PubMed] [Google Scholar]
  128. Uren J. R., Neurath H. Mechanism of activation of bovine procarboxypeptidase A S 5 . Alterations in primary and quaternary structure. Biochemistry. 1972 Nov 21;11(24):4483–4492. doi: 10.1021/bi00774a010. [DOI] [PubMed] [Google Scholar]
  129. Vallet V., Chraibi A., Gaeggeler H. P., Horisberger J. D., Rossier B. C. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature. 1997 Oct 9;389(6651):607–610. doi: 10.1038/39329. [DOI] [PubMed] [Google Scholar]
  130. Valls L. A., Winther J. R., Stevens T. H. Yeast carboxypeptidase Y vacuolar targeting signal is defined by four propeptide amino acids. J Cell Biol. 1990 Aug;111(2):361–368. doi: 10.1083/jcb.111.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Vendrell J., Cuchillo C. M., Avilés F. X. The tryptic activation pathway of monomeric procarboxypeptidase A. J Biol Chem. 1990 Apr 25;265(12):6949–6953. [PubMed] [Google Scholar]
  132. Vernet T., Berti P. J., de Montigny C., Musil R., Tessier D. C., Ménard R., Magny M. C., Storer A. C., Thomas D. Y. Processing of the papain precursor. The ionization state of a conserved amino acid motif within the Pro region participates in the regulation of intramolecular processing. J Biol Chem. 1995 May 5;270(18):10838–10846. doi: 10.1074/jbc.270.18.10838. [DOI] [PubMed] [Google Scholar]
  133. Vernet T., Khouri H. E., Laflamme P., Tessier D. C., Musil R., Gour-Salin B. J., Storer A. C., Thomas D. Y. Processing of the papain precursor. Purification of the zymogen and characterization of its mechanism of processing. J Biol Chem. 1991 Nov 15;266(32):21451–21457. [PubMed] [Google Scholar]
  134. Volanakis J. E., Narayana S. V. Complement factor D, a novel serine protease. Protein Sci. 1996 Apr;5(4):553–564. doi: 10.1002/pro.5560050401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Vu T. K., Liu R. W., Haaksma C. J., Tomasek J. J., Howard E. W. Identification and cloning of the membrane-associated serine protease, hepsin, from mouse preimplantation embryos. J Biol Chem. 1997 Dec 12;272(50):31315–31320. doi: 10.1074/jbc.272.50.31315. [DOI] [PubMed] [Google Scholar]
  136. WINTERSBERGER E., COX D. J., NEURATH H. Bovine pancreatic procarboxypeptidase B. I. Isolation, properties, and activation. Biochemistry. 1962 Nov;1:1069–1078. doi: 10.1021/bi00912a017. [DOI] [PubMed] [Google Scholar]
  137. Wang D., Bode W., Huber R. Bovine chymotrypsinogen A X-ray crystal structure analysis and refinement of a new crystal form at 1.8 A resolution. J Mol Biol. 1985 Oct 5;185(3):595–624. doi: 10.1016/0022-2836(85)90074-9. [DOI] [PubMed] [Google Scholar]
  138. Weinmaster G. Reprolysins and astacins...alive, alive-o. Science. 1998 Jan 16;279(5349):336–337. doi: 10.1126/science.279.5349.336. [DOI] [PubMed] [Google Scholar]
  139. Westphal V., Marcusson E. G., Winther J. R., Emr S. D., van den Hazel H. B. Multiple pathways for vacuolar sorting of yeast proteinase A. J Biol Chem. 1996 May 17;271(20):11865–11870. doi: 10.1074/jbc.271.20.11865. [DOI] [PubMed] [Google Scholar]
  140. White R. T., Damm D., Hancock N., Rosen B. S., Lowell B. B., Usher P., Flier J. S., Spiegelman B. M. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J Biol Chem. 1992 May 5;267(13):9210–9213. [PubMed] [Google Scholar]
  141. Winther J. R., Sørensen P. Propeptide of carboxypeptidase Y provides a chaperone-like function as well as inhibition of the enzymatic activity. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9330–9334. doi: 10.1073/pnas.88.20.9330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Wlodawer A., Erickson J. W. Structure-based inhibitors of HIV-1 protease. Annu Rev Biochem. 1993;62:543–585. doi: 10.1146/annurev.bi.62.070193.002551. [DOI] [PubMed] [Google Scholar]
  143. Wright H. T. The structural puzzle of how serpin serine proteinase inhibitors work. Bioessays. 1996 Jun;18(6):453–464. doi: 10.1002/bies.950180607. [DOI] [PubMed] [Google Scholar]
  144. Yamauchi Y., Stevens J. W., Macon K. J., Volanakis J. E. Recombinant and native zymogen forms of human complement factor D. J Immunol. 1994 Apr 1;152(7):3645–3653. [PubMed] [Google Scholar]

Articles from Protein Science : A Publication of the Protein Society are provided here courtesy of The Protein Society

RESOURCES