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J Biol Chem, Vol. 275, Issue 15, 10995-11001, April 14, 2000
From Biogen, Inc., Cambridge, Massachusetts 02142
We have defined regions in the Sonic hedgehog
(Shh) molecule that are important for Patched (Ptc) receptor binding by
targeting selected surface amino acid residues with probes of diverse
sizes and shapes and assessing the effects of these modifications on function. Eleven amino acid residues that surround the surface of the
protein were chosen for these studies and mutated to cysteine residues.
These cysteines were then selectively modified with thiol-specific
probes, and the modified proteins were tested for hedgehog receptor
binding activity and their ability to induce differentiation of
C3H10T1/2 cells into osteoblasts. Based on these analyses,
approximately one-third of the Shh surface can be modified without
effect on function regardless of the size of the attachment. These
sites are located near to where the C terminus protrudes from the
surface of the protein. All other sites were sensitive to modification,
indicating that the interaction of Shh with its primary receptor Ptc is
mediated over a large surface of the Shh protein. For sites Asn-50 and
Ser-156, function was lost with the smallest of the probes tested,
indicating that these residues are in close proximity to the
Ptc-binding site. The epitope for the neutralizing mAb 5E1 mapped to a
close but distinct region of the structure. The structure-activity data provide a unique view of the interactions between Shh and Ptc that is
not readily attainable by conventional mapping strategies.
Mapping Sonic Hedgehog-Receptor Interactions by Steric
Interference*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Protein
Chemistry, 14 Cambridge Center, Biogen, Inc., Cambridge, MA 02142. Tel.: 617-679-3310; Fax: 617-679-2616.
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