Affiliation:
1. Departments of Biomolecular Chemistry
2. Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706
3. Shriners Hospital for Children, Portland, Oregon 97201
Abstract
ABSTRACT
Bone morphogenetic protein 1 (BMP-1) and mammalian Tolloid (mTLD), two proteinases encoded by
Bmp1
, provide procollagen C-proteinase (pCP) activity that converts procollagens I to III into the major fibrous components of mammalian extracellular matrix (ECM). Yet, although
Bmp1
−/−
mice have aberrant collagen fibrils, they have residual pCP activity, indicative of genetic redundancy. Mammals possess two additional proteinases structurally similar to BMP-1 and mTLD: the genetically distinct mammalian Tolloid-like 1 (mTLL-1) and mTLL-2. Mice lacking the mTLL-1 gene
Tll1
are embryonic lethal but have pCP activity levels similar to those of the wild type, suggesting that mTLL-1 might not be an in vivo pCP. In vitro studies have shown BMP-1 and mTLL-1 capable of cleaving Chordin, an extracellular antagonist of BMP signaling, suggesting that these proteases might also serve to modulate BMP signaling and to coordinate the latter with ECM formation. However, in vivo evidence of roles for BMP-1 and mTLL-1 in BMP signaling in mammals is lacking. To remove functional redundancy obscuring the in vivo functions of BMP-1-related proteases in mammals, we here characterize
Bmp1 Tll1
doubly null mouse embryos. Although these appear morphologically indistinguishable from
Tll1
−/−
embryos, biochemical analysis of cells derived from doubly null embryos shows functional redundancy removed to an extent enabling us to demonstrate that (i) products of
Bmp1
and
Tll1
are responsible for in vivo cleavage of Chordin in mammals and (ii) mTLL-1 is an in vivo pCP that provides residual activity observed in
Bmp1
−/−
embryos. Removal of functional redundancy also enabled use of
Bmp1
−/−
Tll1
−/−
cells in a proteomics approach for identifying novel substrates of
Bmp1
and
Tll1
products.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
100 articles.
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