what-when-how
In Depth Tutorials and Information
CHAPTER
16
SERPINH1
and Osteogenesis
Imperfecta
Jay R. Shapiro
Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
chain assembly.
5
In type I collagen, disulfide bonds are
required for proper folding of the C-propeptide. Type III
collagen (unlike type I collagen) contains disulfide bonds
in the triple helix. Mutations involving the C-propeptide
domain in osteogenesis imperfecta (OI) are discussed in
Chapter 2. In the ER individual pro-alpha chains undergo
multiple post-translational modifications including
hydroxylation of proline and lysine residues, glycosyl-
ation of lysine and hydroxylysine residues and sulfation
of tyrosine residues.
6
As discussed below, HSP47 facili-
tates ER processing by binding to assembled triple-helical
molecules in the pH neutral ER. Collagen-bound HSP47
is freed by lower pH in the Golgi and is rapidly trans-
ported back to the ER by KDEL receptors that recognize
the RDEL motif at the C-terminus of HSP47.
7
INTRODUCTION
The collagens are the most abundant proteins in man
and the major protein in the mammalian extracellular
matrix.
1
As the main structural protein of bone, liga-
ments and tendons, collagens provide mechanical form
and stability, elasticity and strength.
2
Twenty-eight colla-
gen types have been identified to date. All are composed
of three polypeptide α-chains organized in a unique
super-coiled tertiary structure. The collagen type I
heterotrimer is composed of three polypeptide procol-
lagen α-chains: two α-1(I) and one α-2(I) chain, notated
as [α-1(I)]
2
α-2(I). Procollagen chains contain a signal
peptide, an amino-terminal propeptide followed by a
short, nonhelical, N-telopeptide, a central triple helix,
a C-telopeptide and a carboxy-terminal propeptide.
Pro-α1(I) contains 1464 amino acids and the pro-α2(I)
chain contains 1366 amino acids. The central triple-helix
domain contains 1014 amino acids in each chain.
Procollagen α-chains are composed of repeating
(Gly-Xaa-Yaa) triplets, in which the -Xaa and -Yaa posi-
tions are frequently occupied by proline. Most Yaa pro-
lines are 4-hydroxylated and several Xaa prolines are
3-hydroxylated. Pro-986 in both α-1(I) and α-2(I) chains
is 3-hydroxylated under normal conditions but not in
the presence of mutations involving the CRTAP, prolyl-
3-hydroxylase 1 (LEPRE1) and cyclophilin B (PPIB) com-
plex which are associated with a severe OI phenotype.
3,4
The assembly of procollagen α-chains occurs in the
endoplasmic reticulum (ER). Processing from the ER to
the Golgi and subsequent secretion to the extracellular
matrix is critically dependent on proper folding of pro-
collagen chains in the ER. Procollagen α-chain assem-
bly occurs in a zipper-like fashion moving in a C- to
N-terminal direction. C-terminal propeptides are essen-
tial for the trimerization and folding of collagen type I.
As for other proteins, disulfide linkage is essential to
HSP4
7 AS A PROTEIN CHAPER
ONE
HSP47 is a member of the serpin class of proteins
which are serine protease inhibitors. Members of this
group have diverse activity that extends from prote-
ase inhibition to hormone transport and regulation of
chromatin organization.
8
Although HSP47 belongs to
the serpin superfamily, it does not have serine prote-
ase inhibitory activity
9
; HSP47 is induced under stress
conditions through heat shock element-heat shock fac-
tor interaction.
10
HSP47 is expressed in all collagen-
synthesizing cells, and its levels of expression reflect
the amounts of collagen being synthesized in the cor-
responding cell.
11
Possible functions of HSP47 as a
molecular chaperone specific for procollagen include:
stabilization of the natively folded procollagen struc-
ture, inhibition of intracellular degradation of procolla-
gen, the prevention of nascent procollagen chains from
forming aggregates and an effect on the secretion from
the ER to the Golgi compartment.
10,12
