Structural Biology Not So Homologous?

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Signaling by members of the Hedgehog (Hh) family of proteins is important for such processes as tissue patterning and cellular proliferation in organisms from Drosophila to vertebrates. In humans, dysregulation of Sonic hedgehog (Shh, a homolog of Hh) signaling is associated with developmental defects and various cancers. Signaling by Hh is mediated by its N-terminal domain (HhN), which is lipidated and secreted and binds to its receptor Patched (Ptc), which leads to the expression of target genes. HhN also binds to other cell-surface proteins such as Ihog (CDO in mammals), which mediate transcription-dependent and -independent functions of Hh. McLellan et al. solved the x-ray crystal structure of the N-terminal domain of Shh (ShhN) bound to the third fibronectin type III domain of CDO and performed biochemical analyses of the interaction between these two proteins. Despite the similarity in sequence between Hh and Shh and that of their binding partners, the surfaces of Hh and Shh involved in binding to Ihog and CDO, respectively, had almost no overlap. Furthermore, the ShhN-CDO interaction, unlike that between Hh and Ihog, was dependent on the binding of Ca²⁺ to ShhN. The Ca²⁺-binding site was conserved in many Hh-family proteins but appeared to affect only the binding of vertebrate Hh proteins to CDO and other binding partners, including Ptc. In addition, mutations in the genes encoding human Shh and Indian hedgehog (Ihh) that are respectively associated with the developmental disorders holoprosencephaly and brachydactyly type A1 mapped to the Ca²⁺-binding sites of their respective proteins. The authors suggest that the establishment of different binding modes has allowed the evolution of different mechanisms to regulate vertebrate Hh interactions compared with those in Drosophila.

J. S. McLellan, X. Zheng, G. Hauk, R. Ghirlando, P. A. Beachy, D. J. Leahy, The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature 455, 979-983 (2008). [PubMed]

The editors suggest the following Related Resources on Science sites:

In Science Signaling

DATABASE OF CELL SIGNALING
Hedgehog Signaling Pathway

Leni Jacob and Lawrence Lum
Sci. Signal. (Connections Map Pathway), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_19889
 |  Overview »  |  Canonical Pathway »