section 25.11
Collagen Biosynthesis and Its Disorders
589
1. The 4-hydroxylation of at least 100 prolyl residues
per proa chain;
2. The formation of
interchain
disulfide linkages in the
C-terminal propeptide. The latter cannot be formed
until translation is nearly finished. The rate of
disulfide bond and triple-helix formation varies
greatly from one cell type to another—only minutes
in tendon cells that synthesize type I collagen but an
hour in cells that synthesize basement membrane
collagen. These differences in synthesis time may
account for the variations in hydroxylation and
glycosylation. Thus, the extent of posttranslational
modifications depends not only on levels of enzyme
and cofactors but also on the time available.
Translocation and Secretion o f Procollagen
After the procollagen polypeptides are assembled into
a triple helix, they are secreted by the classical route. They
pass through the smooth endoplasmic reticulum and the
Golgi complex, where they are packaged into membranous
vesicles and secreted into the extracellular space by exo-
cytosis. This process requires ATP and may involve micro-
tubules and microfilaments. The conformation of procol-
lagen markedly affects the rate of secretion. Prevention of
the formation of a triple helix (e.g., lack of 4-hydroxylation
due to vitamin C deficiency) leads to the accumulation
of nonhelical propolypeptides within the cistemae of the
rough endoplasmic reticulum and a delayed rate in its
secretion.
Extracellular Posttranslational Modification
Conversion of procollagen to collagen requires at least
two proteases: a procollagen aminoprotease and a procol-
lagen carboxyprotease. The former catalyzes removal of
the N-terminal propeptide and the latter removal of the
C-terminal propeptide. The two enzymes are endopepti-
dases, function at neutral pH, require a bivalent cation
such as Ca2+, and show a preference for the helical con-
formation. There appears to be no preferential order for
the cleavage of the propeptides.
The conversion of procollagen to collagen by removal
of propeptides seems to be essential for the formation of
collagen fibrils. This supposition is supported by stud-
ies of two heritable diseases, one found in humans and
the other in cattle, sheep, and cats. In both, the defect
lies in the removal of N-terminal propeptides and results
in impaired fibril formation. The human disorder is the
type VII variant of Ehlers-Danlos syndrome (Table 25-5).
Affected individuals exhibit marked joint hypermobility,
dislocation of joints, short stature, and minor changes
in skin elasticity. Their skin fibroblasts show normal
N-terminal procollagen protease activity; however, the de-
fect resides in the deletions of the exon that encodes the
protease cleavage sites, thus preventing normal cleavage
of the N-terminal propeptide. In animals, however, the
defect is the N-terminal procollagen protease deficiency,
which produces skin that is easily tom; thus, the disease
is known as
dermatesparaxis.
Formation o f Collagen Fibrils from Ordered
Aggregation o f Collagen Molecules
The collagen molecules formed by removal of the
propeptides spontaneously assemble into fibrils. At this
stage, the fibrils are still immature and lack tensile
strength, which is acquired by cross-linking. The initial
step in cross-link formation is the oxidative deamina-
tion of a-amino groups in certain lysyl and hydroxyly-
syl residues catalyzed by lysyl oxidase. The enzyme is a
copper-dependent (probably cupric) protein, and the reac-
tion requires molecular oxygen and pyridoxal phosphate
for full activity. Only native collagen fibrils function as
substrates.
H N
/
\
H C — ( C H 2) 4— N H 3+ + C
>2
< /
/
%
L y sy l r e s i d u e
N
NH,
/
H \
H
H C — ( C H
2
)
3
— C = 0 + H 20
<
A lly s in e r e s i d u e
In a similar reaction, the hydroxyallysine residue is formed
from hydroxylysine residues. The aldehyde groups react
spontaneously with each other or with amino groups, with
formation of intra- and intermolecular linkages. Lysyl ox-
idase is also involved in the formation of elastin cross-
linkages.
Several collagen disorders result from defects in the
formation of cross-links (Chapter 11). The cross-linking
disorders can be due to a hereditary deficiency of lysyl
oxidase, inhibition of lysyl oxidase, deficiency of cop-
per, defects in the formation of cross-links, or defects
in their stabilization. The genetic deficiency of lysyl oxi-
dase is characterized by
Ehlers-Danlos syndrome type IX
(Table 25-5) and some forms of
cutis laxa.
Type IX Ehlers-
Danlos syndrome patients exhibit extreme extensibility of
the skin, “cigarette-paper” scarring, and easy bruisability.
In cutis laxa, the skin is loose and inelastic and appears
to be too large for the surface it covers. Some affected in-
dividuals exhibit deficiency of lysyl oxidase, presumably
