Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP
- PMID: 19561611
- PMCID: PMC2709225
- DOI: 10.1038/nsmb.1607
Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP
Abstract
Hedgehog (Hh) morphogens have fundamental roles in development, whereas dysregulation of Hh signaling leads to disease. Multiple cell-surface receptors are responsible for transducing and/or regulating Hh signals. Among these, the Hedgehog-interacting protein (Hhip) is a highly conserved, vertebrate-specific inhibitor of Hh signaling. We have solved a series of crystal structures for the human HHIP ectodomain and Desert hedgehog (DHH) in isolation, as well as HHIP in complex with DHH (HHIP-DHH) and Sonic hedgehog (Shh) (HHIP-Shh), with and without Ca2+. The interaction determinants, confirmed by biophysical studies and mutagenesis, reveal previously uncharacterized and distinct functions for the Hh Zn2+ and Ca2+ binding sites--functions that may be common to all vertebrate Hh proteins. Zn2+ makes a key contribution to the Hh-HHIP interface, whereas Ca2+ is likely to prevent electrostatic repulsion between the two proteins, suggesting an important modulatory role. This interplay of several metal binding sites suggests a tuneable mechanism for regulation of Hh signaling.
Figures




Similar articles
-
The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling.Nat Struct Mol Biol. 2009 Jul;16(7):691-7. doi: 10.1038/nsmb.1632. Epub 2009 Jun 28. Nat Struct Mol Biol. 2009. PMID: 19561609
-
Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling.Nat Commun. 2021 Dec 9;12(1):7171. doi: 10.1038/s41467-021-27475-2. Nat Commun. 2021. PMID: 34887403 Free PMC article.
-
Interactions between Hedgehog proteins and their binding partners come into view.Genes Dev. 2010 Sep 15;24(18):2001-12. doi: 10.1101/gad.1951710. Genes Dev. 2010. PMID: 20844013 Free PMC article. Review.
-
The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.Nature. 2008 Oct 16;455(7215):979-83. doi: 10.1038/nature07358. Epub 2008 Sep 14. Nature. 2008. PMID: 18794898 Free PMC article.
-
Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer.Biol Chem. 2010 Aug;391(8):881-92. doi: 10.1515/BC.2010.098. Biol Chem. 2010. PMID: 20536384 Review.
Cited by
-
Highly Conserved C-Terminal Region of Indian Hedgehog N-Fragment Contributes to Its Auto-Processing and Multimer Formation.Biomolecules. 2021 May 25;11(6):792. doi: 10.3390/biom11060792. Biomolecules. 2021. PMID: 34070546 Free PMC article.
-
Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site.J Biol Chem. 2010 Aug 20;285(34):26570-80. doi: 10.1074/jbc.M110.112284. Epub 2010 May 26. J Biol Chem. 2010. PMID: 20504762 Free PMC article.
-
SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts.Nat Commun. 2021 Jul 29;12(1):4611. doi: 10.1038/s41467-021-24819-w. Nat Commun. 2021. PMID: 34326333 Free PMC article.
-
The Binding Mode of the Sonic Hedgehog Inhibitor Robotnikinin, a Combined Docking and QM/MM MD Study.Front Chem. 2017 Oct 23;5:76. doi: 10.3389/fchem.2017.00076. eCollection 2017. Front Chem. 2017. PMID: 29109946 Free PMC article.
-
Structural insights into proteoglycan-shaped Hedgehog signaling.Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16420-5. doi: 10.1073/pnas.1310097110. Epub 2013 Sep 23. Proc Natl Acad Sci U S A. 2013. PMID: 24062467 Free PMC article.
References
-
- Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059–87. - PubMed
-
- Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22:2454–72. - PubMed
-
- Roessler E, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996;14:357–60. - PubMed
-
- Dellovade T, Romer JT, Curran T, Rubin LL. The hedgehog pathway and neurological disorders. Annu Rev Neurosci. 2006;29:539–63. - PubMed
-
- Yauch RL, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455:406–10. - PubMed
Publication types
MeSH terms
Substances
Associated data
- Actions
- Actions
- Actions
- Actions
- Actions
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous