Chemistry Reference
In-Depth Information
proteolysis within the N-terminal region of the core protein, and accumulate
with age.
A predominant function of SLRPs depends on their interaction with fi brillar
collagen that forms the framework of the extracellular matrix. The core proteins
of DCN, BCN, FMOD and LUM interact with the fi brillar collagen to multiple but
different binding sites, while the GAG side- chains form interfi brillar bridges and
stabilize the collagen network. According to John E. Scott ([14] and references cited
therein) these bridges are based on the property of GAG to form 2-fold helices in
solution that are completely complementary, allowing duplexes to form spontane-
ously provided the chains are oriented antiparallel to each other. This type of
interaction also limits access of the collagenase to the unique cleavage site on each
collagen molecule, in this way helping to protect the fi brils from proteolytic
damage.
The interaction of the SLRPs is not confi ned to fi brillar collagen. DCN, FMOD
and LUM have been reported to interact with many other macromolecules,
including type VI, XII and XIV of collagen, fi bronectin and elastin, and growth
factors, such as EGF, transforming growth factor-
.
In the case of DCN the interaction with fi bronectin occurs in a Zn
2+
- dependent
manner and possibly also other members of the SLRPs act as Zn
2+
- binding
proteins. DCN has been shown to possess antitumorogenic properties. Depletion
in SLRP production can infl uence tissue properties. DCN null mice show most
pronounced alteration of skin collagen with a more loose and irregular packed
fi brillar network and a reduced tensile strength leading to an abnormal skin
fragility phenotype. BCN knockout results in an osteoporosis-like phenotype with
a reduced growth rate and a decreased bone mass. Absence of LUM produces
skin laxity and corneal opacity with an increased proportion of abnormally thick
collagen fi brils and delayed corneal epithelial wound healing. In humans a frame-
shift mutation of DCN causes dystrophy of the cornea and a defi ciency of a
galactosyltransferase has been associated with a progeriote form of Ehlers- Danlos
syndrome.
FMOD is a most abundant member of the leucine-rich repeat protein family
and has the highest sequence homology with LUM. The protein core contains four
potential attachment sites for KS all present in the leucine-rich region. The KSs
are short in length (on average nine disaccharide units). Tyrosine sulfation sites
have been identifi ed in the N-terminal part of the molecule.
FMOD is known to interact with type I and II collagen. FMOD is present on
collagen fi bers and tendons. An interaction relevant for the infl ammation reac-
tion is that of FMOD interacting with C1q. In rheumatoid and osteoarthritic
cartilage, degraded fragments of the core proteins of FMOD were reported, but
an increased mRNA and total amount of translated protein indicate that repair
of damaged cartilage may be attempted. In FMOD defi cient mice (FMOD
− / −
) an
early osteoarthritis of the knee and an impaired function of the ligaments were
reported. In explant cultures of cartilage treated with interleukin-1 FMOD frag-
ments cleaved by MMP13 are found. LUM is glycosylated by four
N
- linked KS
β
and tumor necrosis factor-
α
