Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length .
Synthesis and structure
The protein is originally synthesised in an inactive 65
kDa proheparanase form in the
golgi apparatus and transferred to late
/
for transport to the cell-surface. In the lysosome it is
proteolysis into its active form. Proteolytic processing results in the production of three products,
-
a linker peptide
-
an 8 kDa proheparanase fragment and
-
a 50 kDa proheparanase fragment
The 8 kDa and 50 kDa fragments form a
heterodimer and it is this heterodimer that constitutes the active heparanase molecule.
The linker protein is so called because prior to its excision it physically links the 8 kDa and 50 kDa proheparanase fragments. Complete excision of the linker peptide appears to be a prerequisite to the complete activation of the heparanase enzyme.
Crystal structures of both proheparanase and mature heparanase are available, showing that the linker peptide forms a large helical domain which blocks heparan sulfate molecules from interacting with heparanase.
Function
Heparanase has
endoglycosidase activity and cleaves polymeric
heparan sulfate molecules at sites which are internal within the polymeric chain.
The enzyme degrades the heparan sulfate scaffold of the basement membrane and extracellular matrix. It is also associated with the inflammatory process, by allowing the extravasation of activated T lymphocytes.
In ocular surface physiology this activity functions as an off/on switch for the prosecretory mitogen
lacritin. Lacritin binds the cell surface heparan sulfate proteoglycan syndecan-1 only in the presence of active heparanase. Heparanase partially or completely cleaves
heparan sulfate to expose a binding site in the N-terminal 50 amino acids of syndecan-1.
Clinical significance
The successful penetration of the
endothelium that lines the interior surface of
is an important process in the formation of blood borne tumour
metastases.
Heparan sulfate are major constituents of this layer and it has been shown that increased metastatic potential corresponds with increased heparanase activity for a number of
.
Due to the contribution of heparanase activity to metastasis and also to angiogenesis, the inhibition of heparanase activity it is considered to be a potential target for anti-cancer therapies.
Heparanase has been shown to promote arterial thrombosis and stent thrombosis in mouse models due to the cleavage of anti-coagulant heparan sulfate .
Further reading
External links
