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. 2003 Dec 1;376(Pt 2):361–368. doi: 10.1042/BJ20030894

BMP-1-mediated proteolytic processing of alternatively spliced isoforms of collagen type XI.

Ryan J Medeck 1, Sergio Sosa 1, Nicholas Morris 1, Julia Thom Oxford 1
PMCID: PMC1223788  PMID: 12962540

Abstract

Collagen type XI is a minor constituent of heterotypic collagen fibrils of developing cartilage and plays a regulatory role in fibril diameter. Collagen type XI is a heterotrimer composed of the alpha1, alpha2 and alpha3 chains. The mRNA encoding exons 6a, 6b and 8 of the alpha1 chain are expressed alternatively to generate six possible isoforms. The 6b-containing isoform has the most restricted distribution of all isoforms. It is first localized in the developing long bone, where mineralized tissue initially forms, and is later restricted to regions of cartilage that will be subsequently converted into bone. Bone morphogenetic protein 1 (BMP-1) and related proteins cleave procollagens I-III, V and VII, yielding triple-helical molecules that associate into collagen fibrils. The present study demonstrates that the alpha1 chain of collagen type XI can serve as a substrate for BMP-1. In addition, the efficiency with which BMP-1 processes different isoforms of the alpha1 chain varies. The amino acid sequence adjacent to the processing site influences the rate and extent of processing, as do sequences further away. Smaller fragments identified from cartilage extracts indicated that processing by BMP-1, in combination with other processing enzymes, generates small fragments of p6b-containing isoforms.

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Selected References

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

  1. Amano S., Scott I. C., Takahara K., Koch M., Champliaud M. F., Gerecke D. R., Keene D. R., Hudson D. L., Nishiyama T., Lee S. Bone morphogenetic protein 1 is an extracellular processing enzyme of the laminin 5 gamma 2 chain. J Biol Chem. 2000 Jul 28;275(30):22728–22735. doi: 10.1074/jbc.M002345200. [DOI] [PubMed] [Google Scholar]
  2. Beckmann G., Hanke J., Bork P., Reich J. G. Merging extracellular domains: fold prediction for laminin G-like and amino-terminal thrombospondin-like modules based on homology to pentraxins. J Mol Biol. 1998 Feb 6;275(5):725–730. doi: 10.1006/jmbi.1997.1510. [DOI] [PubMed] [Google Scholar]
  3. Bernard M., Yoshioka H., Rodriguez E., Van der Rest M., Kimura T., Ninomiya Y., Olsen B. R., Ramirez F. Cloning and sequencing of pro-alpha 1 (XI) collagen cDNA demonstrates that type XI belongs to the fibrillar class of collagens and reveals that the expression of the gene is not restricted to cartilagenous tissue. J Biol Chem. 1988 Nov 15;263(32):17159–17166. [PubMed] [Google Scholar]
  4. Blaschke U. K., Eikenberry E. F., Hulmes D. J., Galla H. J., Bruckner P. Collagen XI nucleates self-assembly and limits lateral growth of cartilage fibrils. J Biol Chem. 2000 Apr 7;275(14):10370–10378. doi: 10.1074/jbc.275.14.10370. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Borel A., Eichenberger D., Farjanel J., Kessler E., Gleyzal C., Hulmes D. J., Sommer P., Font B. Lysyl oxidase-like protein from bovine aorta. Isolation and maturation to an active form by bone morphogenetic protein-1. J Biol Chem. 2001 Oct 29;276(52):48944–48949. doi: 10.1074/jbc.M109499200. [DOI] [PubMed] [Google Scholar]
  7. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  8. Colige A., Li S. W., Sieron A. L., Nusgens B. V., Prockop D. J., Lapière C. M. cDNA cloning and expression of bovine procollagen I N-proteinase: a new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2374–2379. doi: 10.1073/pnas.94.6.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Davies G. B., Oxford J. T., Hausafus L. C., Smoody B. F., Morris N. P. Temporal and spatial expression of alternative splice-forms of the alpha1(XI) collagen gene in fetal rat cartilage. Dev Dyn. 1998 Sep;213(1):12–26. doi: 10.1002/(SICI)1097-0177(199809)213:1<12::AID-AJA2>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  10. Fernandes R. J., Hirohata S., Engle J. M., Colige A., Cohn D. H., Eyre D. R., Apte S. S. Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis. J Biol Chem. 2001 Jun 14;276(34):31502–31509. doi: 10.1074/jbc.M103466200. [DOI] [PubMed] [Google Scholar]
  11. Gregory K. E., Oxford J. T., Chen Y., Gambee J. E., Gygi S. P., Aebersold R., Neame P. J., Mechling D. E., Bächinger H. P., Morris N. P. Structural organization of distinct domains within the non-collagenous N-terminal region of collagen type XI. J Biol Chem. 2000 Apr 14;275(15):11498–11506. doi: 10.1074/jbc.275.15.11498. [DOI] [PubMed] [Google Scholar]
  12. Imamura Y., Steiglitz B. M., Greenspan D. S. Bone morphogenetic protein-1 processes the NH2-terminal propeptide, and a furin-like proprotein convertase processes the COOH-terminal propeptide of pro-alpha1(V) collagen. J Biol Chem. 1998 Oct 16;273(42):27511–27517. doi: 10.1074/jbc.273.42.27511. [DOI] [PubMed] [Google Scholar]
  13. Jin Y., Cerletti N. Western blotting of transforming growth factor beta 2. Optimization of the electrophoretic transfer. Appl Theor Electrophor. 1992;3(2):85–90. [PubMed] [Google Scholar]
  14. Keene D. R., Oxford J. T., Morris N. P. Ultrastructural localization of collagen types II, IX, and XI in the growth plate of human rib and fetal bovine epiphyseal cartilage: type XI collagen is restricted to thin fibrils. J Histochem Cytochem. 1995 Oct;43(10):967–979. doi: 10.1177/43.10.7560887. [DOI] [PubMed] [Google Scholar]
  15. Kessler E., Fichard A., Chanut-Delalande H., Brusel M., Ruggiero F. Bone morphogenetic protein-1 (BMP-1) mediates C-terminal processing of procollagen V homotrimer. J Biol Chem. 2001 May 17;276(29):27051–27057. doi: 10.1074/jbc.M102921200. [DOI] [PubMed] [Google Scholar]
  16. Kessler E., Takahara K., Biniaminov L., Brusel M., Greenspan D. S. Bone morphogenetic protein-1: the type I procollagen C-proteinase. Science. 1996 Jan 19;271(5247):360–362. doi: 10.1126/science.271.5247.360. [DOI] [PubMed] [Google Scholar]
  17. Kuno K., Terashima Y., Matsushima K. ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix. J Biol Chem. 1999 Jun 25;274(26):18821–18826. doi: 10.1074/jbc.274.26.18821. [DOI] [PubMed] [Google Scholar]
  18. Li S. W., Arita M., Fertala A., Bao Y., Kopen G. C., Långsjö T. K., Hyttinen M. M., Helminen H. J., Prockop D. J. Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. Biochem J. 2001 Apr 15;355(Pt 2):271–278. doi: 10.1042/0264-6021:3550271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Li Y., Lacerda D. A., Warman M. L., Beier D. R., Yoshioka H., Ninomiya Y., Oxford J. T., Morris N. P., Andrikopoulos K., Ramirez F. A fibrillar collagen gene, Col11a1, is essential for skeletal morphogenesis. Cell. 1995 Feb 10;80(3):423–430. doi: 10.1016/0092-8674(95)90492-1. [DOI] [PubMed] [Google Scholar]
  20. Moradi-Améli M., de Chassey B., Farjanel J., van der Rest M. Different splice variants of cartilage alpha1(XI) collagen chain undergo uniform amino-terminal processing. Matrix Biol. 1998 Oct;17(5):393–396. doi: 10.1016/s0945-053x(98)90091-9. [DOI] [PubMed] [Google Scholar]
  21. Morris N. P., Oxford J. T., Davies G. B., Smoody B. F., Keene D. R. Developmentally regulated alternative splicing of the alpha1(XI) collagen chain: spatial and temporal segregation of isoforms in the cartilage of fetal rat long bones. J Histochem Cytochem. 2000 Jun;48(6):725–741. doi: 10.1177/002215540004800601. [DOI] [PubMed] [Google Scholar]
  22. Oxford J. T., Doege K. J., Morris N. P. Alternative exon splicing within the amino-terminal nontriple-helical domain of the rat pro-alpha 1(XI) collagen chain generates multiple forms of the mRNA transcript which exhibit tissue-dependent variation. J Biol Chem. 1995 Apr 21;270(16):9478–9485. doi: 10.1074/jbc.270.16.9478. [DOI] [PubMed] [Google Scholar]
  23. Prockop D. J., Sieron A. L., Li S. W. Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that are essential for procollagen processing probably have important roles in development and cell signaling. Matrix Biol. 1998 Feb;16(7):399–408. doi: 10.1016/s0945-053x(98)90013-0. [DOI] [PubMed] [Google Scholar]
  24. Rattenholl Anke, Pappano William N., Koch Manuel, Keene Douglas R., Kadler Karl E., Sasaki Takako, Timpl Rupert, Burgeson Robert E., Greenspan Daniel S., Bruckner-Tuderman Leena. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen. J Biol Chem. 2002 May 1;277(29):26372–26378. doi: 10.1074/jbc.M203247200. [DOI] [PubMed] [Google Scholar]
  25. Rousseau J. C., Farjanel J., Boutillon M. M., Hartmann D. J., van der Rest M., Moradi-Améli M. Processing of type XI collagen. Determination of the matrix forms of the alpha1(XI) chain. J Biol Chem. 1996 Sep 27;271(39):23743–23748. doi: 10.1074/jbc.271.39.23743. [DOI] [PubMed] [Google Scholar]
  26. Scott I. C., Blitz I. L., Pappano W. N., Imamura Y., Clark T. G., Steiglitz B. M., Thomas C. L., Maas S. A., Takahara K., Cho K. W. Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Dev Biol. 1999 Sep 15;213(2):283–300. doi: 10.1006/dbio.1999.9383. [DOI] [PubMed] [Google Scholar]
  27. Scott I. C., Imamura Y., Pappano W. N., Troedel J. M., Recklies A. D., Roughley P. J., Greenspan D. S. Bone morphogenetic protein-1 processes probiglycan. J Biol Chem. 2000 Sep 29;275(39):30504–30511. doi: 10.1074/jbc.M004846200. [DOI] [PubMed] [Google Scholar]
  28. Seegmiller R., Fraser F. C., Sheldon H. A new chondrodystrophic mutant in mice. Electron microscopy of normal and abnormal chondrogenesis. J Cell Biol. 1971 Mar;48(3):580–593. doi: 10.1083/jcb.48.3.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sussman M. D., Ogle R. C., Balian G. Biosynthesis and processing of collagens in different cartilaginous tissues. J Orthop Res. 1984;2(2):134–142. doi: 10.1002/jor.1100020204. [DOI] [PubMed] [Google Scholar]
  30. Suzuki N., Labosky P. A., Furuta Y., Hargett L., Dunn R., Fogo A. B., Takahara K., Peters D. M., Greenspan D. S., Hogan B. L. Failure of ventral body wall closure in mouse embryos lacking a procollagen C-proteinase encoded by Bmp1, a mammalian gene related to Drosophila tolloid. Development. 1996 Nov;122(11):3587–3595. doi: 10.1242/dev.122.11.3587. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Thom J. R., Morris N. P. Biosynthesis and proteolytic processing of type XI collagen in embryonic chick sterna. J Biol Chem. 1991 Apr 15;266(11):7262–7269. [PubMed] [Google Scholar]
  33. Unsöld Christine, Pappano William N., Imamura Yasutada, Steiglitz Barry M., Greenspan Daniel S. Biosynthetic processing of the pro-alpha 1(V)2pro-alpha 2(V) collagen heterotrimer by bone morphogenetic protein-1 and furin-like proprotein convertases. J Biol Chem. 2001 Dec 12;277(7):5596–5602. doi: 10.1074/jbc.M110003200. [DOI] [PubMed] [Google Scholar]
  34. Uzel M. I., Scott I. C., Babakhanlou-Chase H., Palamakumbura A. H., Pappano W. N., Hong H. H., Greenspan D. S., Trackman P. C. Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures. J Biol Chem. 2001 Apr 19;276(25):22537–22543. doi: 10.1074/jbc.M102352200. [DOI] [PubMed] [Google Scholar]
  35. Wardle F. C., Welch J. V., Dale L. Bone morphogenetic protein 1 regulates dorsal-ventral patterning in early Xenopus embryos by degrading chordin, a BMP4 antagonist. Mech Dev. 1999 Aug;86(1-2):75–85. doi: 10.1016/s0925-4773(99)00114-8. [DOI] [PubMed] [Google Scholar]
  36. Yoshioka H., Ramirez F. Pro-alpha 1(XI) collagen. Structure of the amino-terminal propeptide and expression of the gene in tumor cell lines. J Biol Chem. 1990 Apr 15;265(11):6423–6426. [PubMed] [Google Scholar]

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