title: 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.
abstract: Vertebrate bone morphogenetic protein 1 (BMP-1) and Drosophila Tolloid (TLD) are prototypes of a family of metalloproteases with important roles in various developmental events. BMP-1 affects morphogenesis, at least partly, via biosynthetic processing of fibrillar collagens, while TLD affects dorsal-ventral patterning by releasing TGFbeta-like ligands from latent complexes with the secreted protein Short Gastrulation (SOG). Here, in a screen for additional mammalian members of this family of developmental proteases, we identify novel family member mammalian Tolloid-like 2 (mTLL-2) and compare enzymatic activities and expression domains of all four known mammalian BMP-1/TLD-like proteases [BMP-1, mammalian Tolloid (mTLD), mammalian Tolloid-like 1 (mTLL-1), and mTLL-2]. Despite high sequence similarities, distinct differences are shown in ability to process fibrillar collagen precursors and to cleave Chordin, the vertebrate orthologue of SOG. As previously demonstrated for BMP-1 and mTLD, mTLL-1 is shown to specifically process procollagen C-propeptides at the physiologically relevant site, while mTLL-2 is shown to lack this activity. BMP-1 and mTLL-1 are shown to cleave Chordin, at sites similar to procollagen C-propeptide cleavage sites, and to counteract dorsalizing effects of Chordin upon overexpression in Xenopus embryos. Proteases mTLD and mTLL-2 do not cleave Chordin. Differences in enzymatic activities and expression domains of the four proteases suggest BMP-1 as the major Chordin antagonist in early mammalian embryogenesis and in pre- and postnatal skeletogenesis.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, 1300 University Avenue, Madison, Wisconsin, 53706, USA.
authors.forename: I C
authors.initials: IC
authors.lastname: Scott
authors.forename: I L
authors.initials: IL
authors.lastname: Blitz
authors.forename: W N
authors.initials: WN
authors.lastname: Pappano
authors.forename: Y
authors.initials: Y
authors.lastname: Imamura
authors.forename: T G
authors.initials: TG
authors.lastname: Clark
authors.forename: B M
authors.initials: BM
authors.lastname: Steiglitz
authors.forename: C L
authors.initials: CL
authors.lastname: Thomas
authors.forename: S A
authors.initials: SA
authors.lastname: Maas
authors.forename: K
authors.initials: K
authors.lastname: Takahara
authors.forename: K W
authors.initials: KW
authors.lastname: Cho
authors.forename: D S
authors.initials: DS
authors.lastname: Greenspan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D001842:Bone and Bones / Q000196:embryology / Q000502:physiology; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D004789:Enzyme Activation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D055394:Tolloid-Like Metalloproteinases
chemical_list: D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D006023:Glycoproteins; D019476:Insect Proteins; D036341:Intercellular Signaling Peptides and Proteins; C054234:chordin; D055394:Tolloid-Like Metalloproteinases; C071471:tld protein, Drosophila; D008666:Metalloendopeptidases; C485669:TLL2 protein, human; C121764:Tll2 protein, mouse; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1