what-when-how
In Depth Tutorials and Information
BMP1/TLD (bone morphogenetic protein 1)/tolloid)
proteinases formed by four secreted proteinases encoded
by three different loci; BMP1 and mTLD being two splic-
ing variants encoded by BMP1 ( Figure 19.1 ). 18,19
Recently, two OI patients have been reported by
Lindahl et  al., 20 one with a dominant missense muta-
tion in the COL1A1 C-propeptide cleavage site and one
with a dominant missense mutation in the C-propeptide
cleavage site of COL1A2 . Both patients were described
with a mild phenotype including fractures, radiographic
osteopenia and Wormian bones. Mild tibial bowing
was found in one of the cases. Biochemical analysis of
collagens in cells derived from these patients showed
minimal alteration of the triple-helix folding process,
but delayed processing of type I procollagen secreted
into the media. 20 As PICP is critical for the initiation of
chain folding, these mutations differ from those placed
in the C-terminal propeptide region which interferes
with formation of the triple helix. 21,22 The patients we
reported (see below) have a much more severe pheno-
type than the cleavage site mutation patients described
by Lindahl et  al. 20 This is not surprising since deficient
BMP1/mTLD function is expected to alter C-terminal
processing of both procollagen (I) chains, simultaneously
leading to low levels of fully processed type I collagen,
which in our patients, according to the overexpression
experiments, will depend essentially on the activity of
TLD-like (TLL1 and TLL2) enzymes, although a mini-
mal residual activity of the mutant BMP1/mTLD protein
cannot be completely ruled out. Furthermore, since the
Phe249Leu change described in our patients lies within
the BMP1/mTLD catalytic protease domain, it is highly
probable that processing of other BMP1/mTLD sub-
strates including fibrillar type II and III procollagens,
activation of LOX zymogen, as well as processing of
other secreted factors and extracellular matrix proteins is
compromised. 23
THE BMP1 PROTEIN AND
THE BMP1 GENE
BMP1 and its longer isoform mammalian tolloid pro-
tein (mTLD) are the products of two alternative spliced
transcripts of the same gene BMP1 (MIM 112264) which
is placed on chromosome 8, while the genes for the other
two BMP1/TLD members tolloid-like protein 1 ( TLL1 ,
MIM 606742) and tolloid-like protein 2 ( TLL2 , MIM
606743) are located on chromosomes 4 and 10, respec-
tively. 24-26 The four mammalian BMP1/tolloid proteases
share a similar domain structure and sequence with the
archetype of the family Drosophila tolloid gene, a gene that
is involved in dorsal-ventral patterning of the Drosophila
embryo. 27 This structure consists of a signal peptide fol-
lowed by an N-terminal cleavable protease inhibitor
prodomain that is proteolytically removed by the subtil-
isin-like proprotein convertases in the mature proteins, a
conserved astacin-like protease domain which is shared
by a large family of metalloproteases and a variable
number of complement-uegf-BMP1 (CUB) domains and
epidermal growth factor (EGF)-like domains involved
in protein-protein interactions and in certain cases in
Ca +2 binding ( Figure 19.2 ). 18 Although the four mam-
malian BMP1/tolloid proteins can process procollagen
I C-propeptide, they do not have the same activity, with
BMP1 having the highest C-protease activity, followed
by mTLD and TLL1, with TLL2 having the lowest. 24,30
BMP1/TLD proteases are also known to process other
FIGURE 19.1 Schematic representations of the function of
ADAMTS-2 and BMP1 in the process of procollagen removal of the
N- or C-terminal propeptides.
Signal
peptide
EGF
EGF
CUB
CUB
CUB
CUB
CUB
PROTEASE
F249L
G12R
FIGURE 19.2 Schematic representation of the BMP1 protein: signal peptide, protease domain; CUBs: complement-uegf-BMP1 domains
and EGFs: epidermal growth factor (EGF)-like domains. Mutations described so far are depicted in the protein; G12R in the signal petitde
(reference 28 ) and F249L in the protease domain. 29
Search WWH ::




Custom Search