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Interactions of signaling proteins, growth factors and other proteins with
heparan sulfate: mechanisms and mysteries
#MMPMID26076122
Billings PC
; Pacifici M
Connect Tissue Res
2015[]; 56
(4
): 272-80
PMID26076122
show ga
Heparan sulfate (HS) is a component of cell surface and matrix-associated
proteoglycans (HSPGs) that, collectively, play crucial roles in many physiologic
processes including cell differentiation, organ morphogenesis and cancer. A key
function of HS is to bind and interact with signaling proteins, growth factors,
plasma proteins, immune-modulators and other factors. In doing so, the HS chains
and HSPGs are able to regulate protein distribution, bio-availability and action
on target cells and can also serve as cell surface co-receptors, facilitating
ligand-receptor interactions. These proteins contain an HS/heparin-binding domain
(HBD) that mediates their association and contacts with HS. HBDs are highly
diverse in sequence and predicted structure, contain clusters of basic amino
acids (Lys and Arg) and possess an overall net positive charge, most often within
a consensus Cardin-Weintraub (CW) motif. Interestingly, other domains and
residues are now known to influence protein-HS interactions, as well as
interactions with other glycosaminoglycans, such as chondroitin sulfate. In this
review, we provide a description and analysis of HBDs in proteins including
amphiregulin, fibroblast growth factor family members, heparanase, sclerostin and
hedgehog protein family members. We discuss HBD structural and functional
features and important roles carried out by other protein domains, and also
provide novel conformational insights into the diversity of CW motifs present in
Sonic, Indian and Desert hedgehogs. Finally, we review progress in understanding
the pathogenesis of a rare pediatric skeletal disorder, Hereditary Multiple
Exostoses (HME), characterized by HS deficiency and cartilage tumor formation.
Advances in understanding protein-HS interactions will have broad implications
for basic biology and translational medicine as well as for the development of
HS-based therapeutics.
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