Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.
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...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2009
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| _version_ | 1826265184272908288 |
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| author | Bishop, B Aricescu, A Harlos, K O'Callaghan, C Jones, E Siebold, C |
| author_facet | Bishop, B Aricescu, A Harlos, K O'Callaghan, C Jones, E Siebold, C |
| author_sort | Bishop, B |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:19:40Z |
| format | Journal article |
| id | oxford-uuid:2d5a80e2-df55-46ca-93b2-e5df92d3451e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:19:40Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:2d5a80e2-df55-46ca-93b2-e5df92d3451e2022-03-26T12:42:24ZStructural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2d5a80e2-df55-46ca-93b2-e5df92d3451eEnglishSymplectic Elements at Oxford2009Bishop, BAricescu, AHarlos, KO'Callaghan, CJones, ESiebold, CHedgehog (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. |
| spellingShingle | Bishop, B Aricescu, A Harlos, K O'Callaghan, C Jones, E Siebold, C Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. |
| title | Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. |
| title_full | Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. |
| title_fullStr | Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. |
| title_full_unstemmed | Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. |
| title_short | Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. |
| title_sort | structural insights into hedgehog ligand sequestration by the human hedgehog interacting protein hhip |
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