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. 1995 Jul;4(7):1247–1261. doi: 10.1002/pro.5560040701

The astacin family of metalloendopeptidases.

J S Bond 1, R J Beynon 1
PMCID: PMC2143163  PMID: 7670368

Abstract

The astacin family of metalloendopeptidases was recognized as a novel family of proteases in the 1990s. The crayfish enzyme astacin was the first characterized and is one of the smallest members of the family. More than 20 members of the family have now been identified. They have been detected in species ranging from hydra to humans, in mature and in developmental systems. Proposed functions of these proteases include activation of growth factors, degradation of polypeptides, and processing of extracellular proteins. Astacin family proteases are synthesized with NH2-terminal signal and proenzyme sequences, and many (such as meprins, BMP-1, tolloid) contain multiple domains COOH-terminal to the protease domain. They are either secreted from cells or are plasma membrane-associated enzymes. They have some distinguishing features in addition to the signature sequence in the protease domain: HEXXHXXGFXHEXXRXDR. They have a unique type of zinc binding, with pentacoordination, and a protease domain tertiary structure that contains common attributes with serralysins, matrix metalloendopeptidases, and snake venom proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin and in proteins such as casein and gelatin; and they have arylamidase activity. Meprins are unique proteases in the astacin family, and indeed in the animal kingdom, in their oligomeric structure; they are dimers of disulfide-linked dimers and are highly glycosylated, type I integral membrane proteins that have many attributes of receptors or integrins with adhesion, epidermal growth factor-like, and transmembrane domains. The alpha and beta subunits are differentially expressed and processed to yield latent and active proteases as well as membrane-associated and secreted forms. Meprins represent excellent models of hetero- and homo-oligomeric enzymes that are regulated at the transcriptional and posttranslational levels.

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Selected References

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  1. Barnes K., Ingram J., Kenny A. J. Proteins of the kidney microvillar membrane. Structural and immunochemical properties of rat endopeptidase-2 and its immunohistochemical localization in tissues of rat and mouse. Biochem J. 1989 Dec 1;264(2):335–346. doi: 10.1042/bj2640335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beckmann G., Bork P. An adhesive domain detected in functionally diverse receptors. Trends Biochem Sci. 1993 Feb;18(2):40–41. doi: 10.1016/0968-0004(93)90049-s. [DOI] [PubMed] [Google Scholar]
  3. Bode W., Gomis-Rüth F. X., Huber R., Zwilling R., Stöcker W. Structure of astacin and implications for activation of astacins and zinc-ligation of collagenases. Nature. 1992 Jul 9;358(6382):164–167. doi: 10.1038/358164a0. [DOI] [PubMed] [Google Scholar]
  4. Bode W., Gomis-Rüth F. X., Stöckler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'. FEBS Lett. 1993 Sep 27;331(1-2):134–140. doi: 10.1016/0014-5793(93)80312-i. [DOI] [PubMed] [Google Scholar]
  5. Bond J. S., Beynon R. J. Meprin: a membrane-bound metallo-endopeptidase. Curr Top Cell Regul. 1986;28:263–290. doi: 10.1016/b978-0-12-152828-7.50009-3. [DOI] [PubMed] [Google Scholar]
  6. Bond J. S., Rojas K., Overhauser J., Zoghbi H. Y., Jiang W. The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively. Genomics. 1995 Jan 1;25(1):300–303. doi: 10.1016/0888-7543(95)80142-9. [DOI] [PubMed] [Google Scholar]
  7. Bork P., Beckmann G. The CUB domain. A widespread module in developmentally regulated proteins. J Mol Biol. 1993 May 20;231(2):539–545. doi: 10.1006/jmbi.1993.1305. [DOI] [PubMed] [Google Scholar]
  8. Butler P. E., McKay M. J., Bond J. S. Characterization of meprin, a membrane-bound metalloendopeptidase from mouse kidney. Biochem J. 1987 Jan 1;241(1):229–235. doi: 10.1042/bj2410229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ceci J. D., Kingsley D. M., Silan C. M., Copeland N. G., Jenkins N. A. An interspecific backcross linkage map of the proximal half of mouse chromosome 14. Genomics. 1990 Apr;6(4):673–678. doi: 10.1016/0888-7543(90)90503-m. [DOI] [PubMed] [Google Scholar]
  10. Childs S. R., O'Connor M. B. Two domains of the tolloid protein contribute to its unusual genetic interaction with decapentaplegic. Dev Biol. 1994 Mar;162(1):209–220. doi: 10.1006/dbio.1994.1079. [DOI] [PubMed] [Google Scholar]
  11. Choudry Y., Kenny A. J. Hydrolysis of transforming growth factor-alpha by cell-surface peptidases in vitro. Biochem J. 1991 Nov 15;280(Pt 1):57–60. doi: 10.1042/bj2800057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dumermuth E., Eldering J. A., Grünberg J., Jiang W., Sterchi E. E. Cloning of the PABA peptide hydrolase alpha subunit (PPH alpha) from human small intestine and its expression in COS-1 cells. FEBS Lett. 1993 Dec 13;335(3):367–375. doi: 10.1016/0014-5793(93)80421-p. [DOI] [PubMed] [Google Scholar]
  13. Ehlers M. R., Riordan J. F. Membrane proteins with soluble counterparts: role of proteolysis in the release of transmembrane proteins. Biochemistry. 1991 Oct 22;30(42):10065–10074. doi: 10.1021/bi00106a001. [DOI] [PubMed] [Google Scholar]
  14. Elaroussi M. A., DeLuca H. F. A new member to the astacin family of metalloendopeptidases: a novel 1,25-dihydroxyvitamin D-3-stimulated mRNA from chorioallantoic membrane of quail. Biochim Biophys Acta. 1994 Jan 18;1217(1):1–8. doi: 10.1016/0167-4781(94)90116-3. [DOI] [PubMed] [Google Scholar]
  15. Evans S. V. SETOR: hardware-lighted three-dimensional solid model representations of macromolecules. J Mol Graph. 1993 Jun;11(2):134-8, 127-8. doi: 10.1016/0263-7855(93)87009-t. [DOI] [PubMed] [Google Scholar]
  16. Ferguson E. L., Anderson K. V. Decapentaplegic acts as a morphogen to organize dorsal-ventral pattern in the Drosophila embryo. Cell. 1992 Oct 30;71(3):451–461. doi: 10.1016/0092-8674(92)90514-d. [DOI] [PubMed] [Google Scholar]
  17. Fukagawa M., Suzuki N., Hogan B. L., Jones C. M. Embryonic expression of mouse bone morphogenetic protein-1 (BMP-1), which is related to the Drosophila dorsoventral gene tolloid and encodes a putative astacin metalloendopeptidase. Dev Biol. 1994 May;163(1):175–183. doi: 10.1006/dbio.1994.1133. [DOI] [PubMed] [Google Scholar]
  18. Furie B., Furie B. C. The molecular basis of blood coagulation. Cell. 1988 May 20;53(4):505–518. doi: 10.1016/0092-8674(88)90567-3. [DOI] [PubMed] [Google Scholar]
  19. Gomis-Rüth F. X., Grams F., Yiallouros I., Nar H., Küsthardt U., Zwilling R., Bode W., Stöcker W. Crystal structures, spectroscopic features, and catalytic properties of cobalt(II), copper(II), nickel(II), and mercury(II) derivatives of the zinc endopeptidase astacin. A correlation of structure and proteolytic activity. J Biol Chem. 1994 Jun 24;269(25):17111–17117. [PubMed] [Google Scholar]
  20. Gorbea C. M., Flannery A. V., Bond J. S. Homo- and heterotetrameric forms of the membrane-bound metalloendopeptidases meprin A and B. Arch Biochem Biophys. 1991 Nov 1;290(2):549–553. doi: 10.1016/0003-9861(91)90580-c. [DOI] [PubMed] [Google Scholar]
  21. Gorbea C. M., Marchand P., Jiang W., Copeland N. G., Gilbert D. J., Jenkins N. A., Bond J. S. Cloning, expression, and chromosomal localization of the mouse meprin beta subunit. J Biol Chem. 1993 Oct 5;268(28):21035–21043. [PubMed] [Google Scholar]
  22. Hall J. L., Sterchi E. E., Bond J. S. Biosynthesis and degradation of meprins, kidney brush border proteinases. Arch Biochem Biophys. 1993 Nov 15;307(1):73–77. doi: 10.1006/abbi.1993.1562. [DOI] [PubMed] [Google Scholar]
  23. Hwang S. P., Partin J. S., Lennarz W. J. Characterization of a homolog of human bone morphogenetic protein 1 in the embryo of the sea urchin, Strongylocentrotus purpuratus. Development. 1994 Mar;120(3):559–568. doi: 10.1242/dev.120.3.559. [DOI] [PubMed] [Google Scholar]
  24. Jiang W., Bond J. S. Families of metalloendopeptidases and their relationships. FEBS Lett. 1992 Nov 9;312(2-3):110–114. doi: 10.1016/0014-5793(92)80916-5. [DOI] [PubMed] [Google Scholar]
  25. Jiang W., Gorbea C. M., Flannery A. V., Beynon R. J., Grant G. A., Bond J. S. The alpha subunit of meprin A. Molecular cloning and sequencing, differential expression in inbred mouse strains, and evidence for divergent evolution of the alpha and beta subunits. J Biol Chem. 1992 May 5;267(13):9185–9193. [PubMed] [Google Scholar]
  26. Jiang W., Sadler P. M., Jenkins N. A., Gilbert D. J., Copeland N. G., Bond J. S. Tissue-specific expression and chromosomal localization of the alpha subunit of mouse meprin A. J Biol Chem. 1993 May 15;268(14):10380–10385. [PubMed] [Google Scholar]
  27. Johnson G. D., Hersh L. B. Cloning a rat meprin cDNA reveals the enzyme is a heterodimer. J Biol Chem. 1992 Jul 5;267(19):13505–13512. [PubMed] [Google Scholar]
  28. Johnson G. D., Hersh L. B. Expression of meprin subunit precursors. Membrane anchoring through the beta subunit and mechanism of zymogen activation. J Biol Chem. 1994 Mar 11;269(10):7682–7688. [PubMed] [Google Scholar]
  29. Kaushal G. P., Walker P. D., Shah S. V. An old enzyme with a new function: purification and characterization of a distinct matrix-degrading metalloproteinase in rat kidney cortex and its identification as meprin. J Cell Biol. 1994 Sep;126(5):1319–1327. doi: 10.1083/jcb.126.5.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kennelly P. J., Krebs E. G. Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J Biol Chem. 1991 Aug 25;266(24):15555–15558. [PubMed] [Google Scholar]
  31. Kitamoto Y., Yuan X., Wu Q., McCourt D. W., Sadler J. E. Enterokinase, the initiator of intestinal digestion, is a mosaic protease composed of a distinctive assortment of domains. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7588–7592. doi: 10.1073/pnas.91.16.7588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lee K. S., Yasumasu S., Nomura K., Iuchi I. HCE, a constituent of the hatching enzymes of Oryzias latipes embryos, releases unique proline-rich polypeptides from its natural substrate, the hardened chorion. FEBS Lett. 1994 Feb 21;339(3):281–284. doi: 10.1016/0014-5793(94)80431-1. [DOI] [PubMed] [Google Scholar]
  33. Lepage T., Ghiglione C., Gache C. Spatial and temporal expression pattern during sea urchin embryogenesis of a gene coding for a protease homologous to the human protein BMP-1 and to the product of the Drosophila dorsal-ventral patterning gene tolloid. Development. 1992 Jan;114(1):147–163. doi: 10.1242/dev.114.1.147. [DOI] [PubMed] [Google Scholar]
  34. Lepage T., Sardet C., Gache C. Spatial expression of the hatching enzyme gene in the sea urchin embryo. Dev Biol. 1992 Mar;150(1):23–32. doi: 10.1016/0012-1606(92)90004-z. [DOI] [PubMed] [Google Scholar]
  35. Marchand P., Tang J., Bond J. S. Membrane association and oligomeric organization of the alpha and beta subunits of mouse meprin A. J Biol Chem. 1994 May 27;269(21):15388–15393. [PubMed] [Google Scholar]
  36. Marchand P., Tang J., Johnson G. D., Bond J. S. COOH-terminal proteolytic processing of secreted and membrane forms of the alpha subunit of the metalloprotease meprin A. Requirement of the I domain for processing in the endoplasmic reticulum. J Biol Chem. 1995 Mar 10;270(10):5449–5456. doi: 10.1074/jbc.270.10.5449. [DOI] [PubMed] [Google Scholar]
  37. Matrisian L. M. The matrix-degrading metalloproteinases. Bioessays. 1992 Jul;14(7):455–463. doi: 10.1002/bies.950140705. [DOI] [PubMed] [Google Scholar]
  38. Maéno M., Xue Y., Wood T. I., Ong R. C., Kung H. F. Cloning and expression of cDNA encoding Xenopus laevis bone morphogenetic protein-1 during early embryonic development. Gene. 1993 Dec 8;134(2):257–261. doi: 10.1016/0378-1119(93)90103-a. [DOI] [PubMed] [Google Scholar]
  39. Milhiet P. E., Corbeil D., Simon V., Kenny A. J., Crine P., Boileau G. Expression of rat endopeptidase-24.18 in COS-1 cells: membrane topology and activity. Biochem J. 1994 May 15;300(Pt 1):37–43. doi: 10.1042/bj3000037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nguyen T., Jamal J., Shimell M. J., Arora K., O'Connor M. B. Characterization of tolloid-related-1: a BMP-1-like product that is required during larval and pupal stages of Drosophila development. Dev Biol. 1994 Dec;166(2):569–586. doi: 10.1006/dbio.1994.1338. [DOI] [PubMed] [Google Scholar]
  41. Padgett R. W., Wozney J. M., Gelbart W. M. Human BMP sequences can confer normal dorsal-ventral patterning in the Drosophila embryo. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2905–2909. doi: 10.1073/pnas.90.7.2905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rawlings N. D., Barrett A. J. Evolutionary families of peptidases. Biochem J. 1993 Feb 15;290(Pt 1):205–218. doi: 10.1042/bj2900205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Reynolds S. D., Angerer L. M., Palis J., Nasir A., Angerer R. C. Early mRNAs, spatially restricted along the animal-vegetal axis of sea urchin embryos, include one encoding a protein related to tolloid and BMP-1. Development. 1992 Mar;114(3):769–786. doi: 10.1242/dev.114.3.769. [DOI] [PubMed] [Google Scholar]
  44. Sato S. M., Sargent T. D. Molecular approach to dorsoanterior development in Xenopus laevis. Dev Biol. 1990 Jan;137(1):135–141. doi: 10.1016/0012-1606(90)90014-a. [DOI] [PubMed] [Google Scholar]
  45. Sim R. B., Day A. J., Moffatt B. E., Fontaine M. Complement factor I and cofactors in control of complement system convertase enzymes. Methods Enzymol. 1993;223:13–35. doi: 10.1016/0076-6879(93)23035-l. [DOI] [PubMed] [Google Scholar]
  46. Spencer-Dene B., Thorogood P., Nair S., Kenny A. J., Harris M., Henderson B. Distribution of, and a putative role for, the cell-surface neutral metallo-endopeptidases during mammalian craniofacial development. Development. 1994 Nov;120(11):3213–3226. doi: 10.1242/dev.120.11.3213. [DOI] [PubMed] [Google Scholar]
  47. Sterchi E. E., Naim H. Y., Lentze M. J., Hauri H. P., Fransen J. A. N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase: a metalloendopeptidase of the human intestinal microvillus membrane which degrades biologically active peptides. Arch Biochem Biophys. 1988 Aug 15;265(1):105–118. doi: 10.1016/0003-9861(88)90376-1. [DOI] [PubMed] [Google Scholar]
  48. Stöcker W., Gomis-Rüth F. X., Bode W., Zwilling R. Implications of the three-dimensional structure of astacin for the structure and function of the astacin family of zinc-endopeptidases. Eur J Biochem. 1993 May 15;214(1):215–231. doi: 10.1111/j.1432-1033.1993.tb17915.x. [DOI] [PubMed] [Google Scholar]
  49. Stöcker W., Grams F., Baumann U., Reinemer P., Gomis-Rüth F. X., McKay D. B., Bode W. The metzincins--topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci. 1995 May;4(5):823–840. doi: 10.1002/pro.5560040502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Stöcker W., Ng M., Auld D. S. Fluorescent oligopeptide substrates for kinetic characterization of the specificity of Astacus protease. Biochemistry. 1990 Nov 13;29(45):10418–10425. doi: 10.1021/bi00497a018. [DOI] [PubMed] [Google Scholar]
  51. Takahara K., Lyons G. E., Greenspan D. S. Bone morphogenetic protein-1 and a mammalian tolloid homologue (mTld) are encoded by alternatively spliced transcripts which are differentially expressed in some tissues. J Biol Chem. 1994 Dec 23;269(51):32572–32578. [PubMed] [Google Scholar]
  52. Tarentino A. L., Quinones G., Grimwood B. G., Hauer C. R., Plummer T. H., Jr Molecular cloning and sequence analysis of flavastacin: an O-glycosylated prokaryotic zinc metalloendopeptidase. Arch Biochem Biophys. 1995 May 10;319(1):281–285. doi: 10.1006/abbi.1995.1293. [DOI] [PubMed] [Google Scholar]
  53. Wolz R. L., Bond J. S. Meprins A and B. Methods Enzymol. 1995;248:325–345. doi: 10.1016/0076-6879(95)48022-6. [DOI] [PubMed] [Google Scholar]
  54. Wolz R. L., Harris R. B., Bond J. S. Mapping the active site of meprin-A with peptide substrates and inhibitors. Biochemistry. 1991 Aug 27;30(34):8488–8493. doi: 10.1021/bi00098a029. [DOI] [PubMed] [Google Scholar]
  55. Wozney J. M., Rosen V., Celeste A. J., Mitsock L. M., Whitters M. J., Kriz R. W., Hewick R. M., Wang E. A. Novel regulators of bone formation: molecular clones and activities. Science. 1988 Dec 16;242(4885):1528–1534. doi: 10.1126/science.3201241. [DOI] [PubMed] [Google Scholar]
  56. Yamaguchi T., Fukase M., Sugimoto T., Kido H., Chihara K. Purification of meprin from human kidney and its role in parathyroid hormone degradation. Biol Chem Hoppe Seyler. 1994 Dec;375(12):821–824. [PubMed] [Google Scholar]
  57. Yamaguchi T., Kido H., Fukase M., Fujita T., Katunuma N. A membrane-bound metallo-endopeptidase from rat kidney hydrolyzing parathyroid hormone. Purification and characterization. Eur J Biochem. 1991 Sep 1;200(2):563–571. doi: 10.1111/j.1432-1033.1991.tb16219.x. [DOI] [PubMed] [Google Scholar]
  58. Yamaguchi T., Kido H., Kitazawa R., Kitazawa S., Fukase M., Katunuma N. A membrane-bound metallo-endopeptidase from rat kidney: its immunological characterization. J Biochem. 1993 Mar;113(3):299–303. doi: 10.1093/oxfordjournals.jbchem.a124042. [DOI] [PubMed] [Google Scholar]
  59. Yasumasu S., Iuchi I., Yamagami K. Isolation and some properties of low choriolytic enzyme (LCE), a component of the hatching enzyme of the teleost, Oryzias latipes. J Biochem. 1989 Feb;105(2):212–218. doi: 10.1093/oxfordjournals.jbchem.a122641. [DOI] [PubMed] [Google Scholar]
  60. Yasumasu S., Iuchi I., Yamagami K. Purification and partial characterization of high choriolytic enzyme (HCE), a component of the hatching enzyme of the teleost, Oryzias latipes. J Biochem. 1989 Feb;105(2):204–211. doi: 10.1093/oxfordjournals.jbchem.a122640. [DOI] [PubMed] [Google Scholar]
  61. Yasumasu S., Katow S., Hamazaki T. S., Iuchi I., Yamagami K. Two constituent proteases of a teleostean hatching enzyme: concurrent syntheses and packaging in the same secretory granules in discrete arrangement. Dev Biol. 1992 Feb;149(2):349–356. doi: 10.1016/0012-1606(92)90290-w. [DOI] [PubMed] [Google Scholar]
  62. Yasumasu S., Katow S., Umino Y., Iuchi I., Yamagami K. A unique proteolytic action of HCE, a constituent protease of a fish hatching enzyme: tight binding to its natural substrate, egg envelope. Biochem Biophys Res Commun. 1989 Jul 14;162(1):58–63. doi: 10.1016/0006-291x(89)91961-x. [DOI] [PubMed] [Google Scholar]
  63. Yoshiura K., Tamura T., Hong H. S., Ohta T., Soejima H., Kishino T., Jinno Y., Niikawa N. Mapping of the bone morphogenetic protein 1 gene (BMP1) to 8p21: removal of BMP1 from candidacy for the bone disorder in Langer-Giedion syndrome. Cytogenet Cell Genet. 1993;64(3-4):208–209. doi: 10.1159/000133577. [DOI] [PubMed] [Google Scholar]

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