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CHAPTER
6
The Collagen Folding Machinery:
Biosynthesis and Post-Translational
Mod
iications of Colla
gens
Elena Pokidysheva
1,2
, Kazunori Mizuno
1
and Hans Peter
Bächinger
1,2
1
Shriners Hospitals for Children, Portland, OR, USA,
2
Oregon Health & Science University, Portland, OR, USA
INTRODUCTION
PR
OCOLLAGEN BIOSYNTHE
SIS
The biosynthesis of collagens is a complex process
in which even slight disturbances lead to a number of
severe diseases. Some of the collagen-related genetic
diseases include Ehlers-Danlos syndrome, chondro-
dysplasias, Alport syndrome, Bethlem myopathy, epi-
dermolysis bullosa, Knobloch syndrome, some cases of
osteoporosis, arterial aneurysms, intervertebral disc dis-
ease and osteogenesis imperfecta (OI).
1
In this chapter
we aim to give a review of how non-collagenous rough
endoplasmic reticulum (rER) resident proteins relate to
OI. About 90% of the OI cases are due to heterozygous
mutations in either the α1 or α2 chains of type I procol-
lagen (
COL1A1
and
COL1A2
).
2
Until recently, the role of
post-translational modifications of type I collagen in OI
was not appreciated enough. During the last few years
a number of non-collagenous genes have been shown
to cause recessive forms of the disease.
3-18
These genes
code for the proteins that play important roles during
collagen folding and post-translational modifications. In
this chapter we will summarize the effects of alterations
in these genes on the folding of the triple helix and post-
translational modifications of type I collagen. Molecular
mechanisms involved in the pathogenesis of the OI will
be discussed. Our current understanding of recessive OI
represents a classical example of how basic biochemical
research can translate into the clinic by providing sug-
gestions for new therapeutic approaches.
Every protein has to be properly folded and modified
to become functional. Basic steps in successful protein
production and maturation include: synthesis, post-
translational modifications, folding, quality control, and
transport. These processes occur in different cell com-
partments. The rough endoplasmic reticulum and Golgi
are the home of folding and post-translational modifi-
cations for secreted proteins.
19
Maturation of collagens
requires all these steps to proceed smoothly. Recent data
show that altered post-translational modifications can
result in OI.
A schematic representation of the collagen biosynthe-
sis is given in
Figure 6.1
. Important steps in this process
can be summarized as following:
1.
Translocation of the emerging amino-terminal end of
the pro-α-chains into the rER.
2.
Once the synthesis of the amino-terminal propeptide
is completed it folds and forms intra-chain disulfide
bonds. At this stage heat shock protein 47 (Hsp47)
may specifically bind to the amino-terminal
propeptide,
20,21
but additionally it has binding sites
along the triple helical portion of the molecule.
20,22
3.
Synthesis continues and some of the proline residues
become hydroxylated by prolyl 4-hydroxylase
23
and prolyl 3-hydroxylase.
24
During the continued
synthesis of the major helical sequence, some
