Berry R, Jowitt TA, Ferrand J, Roessle M, Grossmann JG, Canty-Laird EG, Kammerer RA, Kadler KK, Baldock C. 2009. Role of dimerization and substrate exclusion in the regulation of bone morphogenetic protein-1 and mammalian tolloid. Proceedings of the National Academy of Sciences of the United States of America 106:8561-8566.pubmed
One of the most fundamental processes in biology is the development of the embryo. A part of this process is the formation of the embryo’s back and belly surfaces. This is called dorso-ventral patterning.
The bone morphogenetic protein (BMP)-1/tolloid metalloproteinases are evolutionarily conserved enzymes that are fundamental to dorsal-ventral patterning. They are also involved in the formation of new tissues, otherwise called tissue morphogenesis. However, a detailed understanding of tissue assembly and embryonic patterning still requires considerably more research. In this paper, work from the Baldock lab has shed new light on developmental patterning by showing how this class of proteinases recognize and cleave their substrates.
Although BMP-1 and mammalian tolloid are very closely related because they are splice variants, it was puzzling why BMP-1, which lacks 3 of the 7 non-catalytic domains present in all other family members, is the most effective proteinase within this family of enzymes. Using a combination of techniques to determine the shapes and biophysical properties of these proteins in solution, this study demonstrated that tolloid, but not BMP-1, forms a calcium-ion-dependent dimer under physiological conditions. Moreover the EGF2 domain, which is absent in BMP-1, is critical to the formation of the dimer. Based on a combination of structural and functional data, tolloid activity was shown to be regulated by a substrate exclusion mechanism.
The study reveals how alternative splicing of the Bmp1 gene produces two proteinases with differing biological activities. It therefore has broad implications for understanding how this class of proteinases are involved in signalling, tissue assembly, and embryonic development.