Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid

Richard Berry, Thomas A Jowitt, Johanna Ferrand, Manfred Roessle, J. Günter Grossmann, Elizabeth G. Canty-Laird, Richard A. Kammerer, Karl E. Kadler, Clair Baldock

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

Abstract

The bone morphogenetic protein (BMP)-1/tolloid metalloproteinases are evolutionarily conserved enzymes that are fundamental to dorsal-ventral patterning and tissue morphogenesis. The lack of knowledge regarding how these proteinases recognize and cleave their substrates represents a major hurdle to understanding tissue assembly and embryonic patterning. Although BMP-1 and mammalian tolloid (mTLD) are splice variants, it is puzzling why BMP-1, which lacks 3 of the 7 noncatalytic domains present in all other family members, is the most effective proteinase. Using a combination of single-particle electron microscopy, small-angle X-ray scattering, and other biophysical measurements in solution, we show that mTLD, but not BMP-1, forms a calciumion-dependent dimer under physiological conditions. Using a domain deletion approach, we provide evidence that EGF2, which is absent in BMP-1, is critical to the formation of the dimer. Based on a combination of structural and functional data, we propose that mTLD activity is regulated by a substrate exclusion mechanism. These results provide a mechanistic insight into how alternative splicing of the Bmp1 gene produces 2 proteinases with differing biological activities and have broad implications for regulation of BMP-1/mTLD and related proteinases during BMP signaling and tissue assembly.

Original languageEnglish
Pages (from-to)8561-8566
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number21
DOIs
Publication statusPublished - 26 May 2009
Externally publishedYes

Keywords

  • Chordin
  • Procollagen C-proteinase
  • Small angle x-ray scattering

Cite this