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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1543-1550
CHEMOKINES
Characterization of the binding site on heparan sulfate for
macrophage inflammatory protein 1
Sally E. Stringer,
Mark J. Forster,
Barbara Mulloy,
Christopher R. Bishop,
Gerard
J. Graham, and
John T. Gallagher
From the Paterson Institute for Cancer Research,
Manchester; the National Institute for Biological Standards and
Control, Potters Bar; and the Beatson Institute for Cancer Research,
Glasgow, United Kingdom.
The CC chemokine macrophage inflammatory protein 1 (MIP1) is
a key regulator of the proliferation and differentiation of hematopoietic progenitor cells. The activity of MIP1 appears to be
modulated by its binding to heparan sulfate (HS) proteoglycans, ubiquitous components of the mammalian cell surface and extracellular matrix. In this study we show that HS has highest affinity for the
dimeric form of MIP1. The predominantly dimeric BB10010 MIP1 interacts with an 8.3-kDa sequence in the HS polysaccharide chain, which it protects from degradation by heparinase enzymes. The major
structural motif of this HS fragment appears to consist of 2 sulfate-rich S-domains separated by a short central N-acetylated region. The optimum lengths of these S-domains seem to be 12 to 14 saccharides. We propose that this binding fragment may wrap around the
MIP1 dimer in a horseshoe shape, facilitating the interaction of the
S-domains with the heparin-binding domains on each monomer. Molecular
modeling suggests that these S-domains are likely to interact with
basic residues Arg 17, Arg 45, and Arg 47 and possibly with Lys 44 on
MIP1 and that the interconnecting N-acetylated region is of
sufficient length to allow the 2 S-domains to bind to these sites on
opposite faces of the dimer. Elucidation of the structure of the
HS-binding site for MIP1 may enable us to devise ways of enhancing
its myeloprotective or peripheral blood stem cell mobilization
properties, which can be used to improve cancer chemotherapy treatments.
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