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CHAPTER
7
Collagen Structure, Folding and
Function
Elena Makareeva and Sergey Leikin
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, MD, USA
INTRODUCTION: COLLAGEN ROLE IN
OST EOGENESIS IMPERFECTA (OI)
TYPE I COLLAGEN
Type I collagen is by far the most abundant protein
in all vertebrates. It assembles into fibers that form the
structural and mechanical scaffold (matrix) of bone,
skin, tendons, cornea, blood vessel walls and other con-
nective tissues. Heterotrimers of two α1(I) and one α2(I)
chains are the dominant isoform of type I collagen.
Homotrimers of three α1(I) chains are found in fetal tis-
sues, 19 tumors 20-25 and some fibrotic lesions. 26-28 The
homotrimeric isoform is more resistant to cleavage by
collagenases, which might explain its accumulation
and functional role in tumors and fibrotic lesions. 25,29
However, this isoform becomes prevalent in other tissues
only in extremely rare disorders associated with COL1A2
deficiency.30-32 30-32
Type I collagen is synthesized as a procollagen pre-
cursor, which consists of an N-terminal propeptide,
central collagen domain and C-terminal propeptide.
Procollagen chains are cotranslationally translocated
into the lumen of rough endoplasmic reticulum
(ER). After post-translational modification and fold-
ing in the ER, procollagen molecules are transported
through Golgi and secreted from the cell. N- and
C-propeptide cleavage produces a 300 nm-long col-
lagen triple helix bounded by short terminal pep-
tides (telopeptides). These mature collagen molecules
are then assembled into fibers, often together with a
smaller fraction of molecules of type III, V and XI col-
lagens ( Figure 7.1 ). 33-35
Most OI cases are caused by dominantly inherited
mutations in COL1A1 and COL1A2 genes, which encode
the α1(I) and α2(I) chains of type I collagen. 1 Recently
discovered mutations in other genes, which cause reces-
sively inherited OI, further emphasize the central role of
type I collagen in this disorder. Among the latter genes,
CRTAP , LEPRE1 , PPIB , SERPINH1 , FKBP10 , PLOD2 and
BMP1 encode proteins essential for normal production or
function of type I collagen. 2-15 SERPINF1 encodes a pro-
tein that has high binding affinity to type I collagen and
might be involved in regulating type I collagen function,
although no defects in type I collagen biosynthesis have
been detected in cultures of SERPINF1 -deicient dermal
fibroblasts from patients with type VI OI. 16,17 In fact, the
only report of OI without direct links to type I collagen
describes a single patient with a frameshift mutation
in the SP7 gene, which encodes a transcription factor
involved in osteoblast differentiation and function. 18
All these recent advances in OI genetics underscore the
long-held belief that understanding regulation of type I
collagen biosynthesis, structure and function is crucial for
understanding the underlying causes and treatment of OI.
Several other chapters in this topic discuss protein machin-
ery involved in collagen biosynthesis, including the protein
deficiencies which cause the newly discovered recessive
forms of OI. In the present chapter, we focus on type I col-
lagen properties that appear to be important in OI.
 
 
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