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==Crystal structure of Hedgehog-interacting protein (HHIP) and Sonic hedgehog (SHH) complex==
==Crystal structure of Hedgehog-interacting protein (HHIP) and Sonic hedgehog (SHH) complex==
<StructureSection load='3ho5' size='340' side='right' caption='[[3ho5]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
<StructureSection load='3ho5' size='340' side='right'caption='[[3ho5]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3ho5]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HO5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HO5 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3ho5]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HO5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HO5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.01&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ho3|3ho3]], [[3ho4|3ho4]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HHIP, HIP, UNQ5825/PRO19644 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), SHH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ho5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ho5 OCA], [https://pdbe.org/3ho5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ho5 RCSB], [https://www.ebi.ac.uk/pdbsum/3ho5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ho5 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ho5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ho5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ho5 RCSB], [http://www.ebi.ac.uk/pdbsum/3ho5 PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN]] Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM:[http://omim.org/entry/611638 611638]]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).<ref>PMID:12503095</ref>  Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:[http://omim.org/entry/142945 142945]]. Holoprosencephaly (HPE) [MIM:[http://omim.org/entry/236100 236100]] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.<ref>PMID:8896572</ref> <ref>PMID:9302262</ref> <ref>PMID:10441331</ref> <ref>PMID:10556296</ref> <ref>PMID:11479728</ref> <ref>PMID:15107988</ref> <ref>PMID:15221788</ref> <ref>PMID:15942952</ref> <ref>PMID:15942953</ref> <ref>PMID:16282375</ref> <ref>PMID:17001669</ref> <ref>PMID:19603532</ref>  Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:[http://omim.org/entry/147250 147250]]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.<ref>PMID:11471164</ref> <ref>PMID:15103725</ref>  Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:[http://omim.org/entry/174500 174500]]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.<ref>PMID:12837695</ref> 
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/HHIP_HUMAN HHIP_HUMAN]] Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.<ref>PMID:11472839</ref> <ref>PMID:19561609</ref> [[http://www.uniprot.org/uniprot/SHH_HUMAN SHH_HUMAN]] Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction (By similarity).
[https://www.uniprot.org/uniprot/HHIP_HUMAN HHIP_HUMAN] Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.<ref>PMID:11472839</ref> <ref>PMID:19561609</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ho/3ho5_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ho/3ho5_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3ho5 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 3ho5" style="background-color:#fffaf0;"></div>
==See Also==
*[[Sonic hedgehog 3D structures|Sonic hedgehog 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Bosanac, I]]
[[Category: Large Structures]]
[[Category: Hymowitz, S G]]
[[Category: Bosanac I]]
[[Category: Autocatalytic cleavage]]
[[Category: Hymowitz SG]]
[[Category: Calcium cation]]
[[Category: Cell membrane]]
[[Category: Developmental protein]]
[[Category: Disease mutation]]
[[Category: Disulfide bond]]
[[Category: Egf domain]]
[[Category: Egf-like domain]]
[[Category: Glycoprotein]]
[[Category: Holoprosencephaly]]
[[Category: Hydrolase]]
[[Category: Lipoprotein]]
[[Category: Membrane]]
[[Category: Microphthalmia]]
[[Category: Palmitate]]
[[Category: Protease]]
[[Category: Receptor ectodomain]]
[[Category: Secreted]]
[[Category: Signaling protein]]
[[Category: Six-bladed-propeller domain]]
[[Category: Zinc cation]]

Latest revision as of 08:52, 17 October 2024

Crystal structure of Hedgehog-interacting protein (HHIP) and Sonic hedgehog (SHH) complexCrystal structure of Hedgehog-interacting protein (HHIP) and Sonic hedgehog (SHH) complex

Structural highlights

3ho5 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.01Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HHIP_HUMAN Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.[1] [2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Hedgehog (Hh) signaling is crucial for many aspects of embryonic development, whereas dysregulation of this pathway is associated with several types of cancer. Hedgehog-interacting protein (Hhip) is a surface receptor antagonist that is equipotent against all three mammalian Hh homologs. The crystal structures of human HHIP alone and bound to Sonic hedgehog (SHH) now reveal that HHIP is comprised of two EGF domains and a six-bladed beta-propeller domain. In the complex structure, a critical loop from HHIP binds the pseudo active site groove of SHH and directly coordinates its Zn2+ cation. Notably, sequence comparisons of this SHH binding loop with the Hh receptor Patched (Ptc1) ectodomains and HHIP- and PTC1-peptide binding studies suggest a 'patch for Patched' at the Shh pseudo active site; thus, we propose a role for Hhip as a structural decoy receptor for vertebrate Hh.

The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling.,Bosanac I, Maun HR, Scales SJ, Wen X, Lingel A, Bazan JF, de Sauvage FJ, Hymowitz SG, Lazarus RA Nat Struct Mol Biol. 2009 Jul;16(7):691-7. Epub 2009 Jun 28. PMID:19561609[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Pathi S, Pagan-Westphal S, Baker DP, Garber EA, Rayhorn P, Bumcrot D, Tabin CJ, Blake Pepinsky R, Williams KP. Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech Dev. 2001 Aug;106(1-2):107-17. PMID:11472839
  2. ↑ Bosanac I, Maun HR, Scales SJ, Wen X, Lingel A, Bazan JF, de Sauvage FJ, Hymowitz SG, Lazarus RA. 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. Epub 2009 Jun 28. PMID:19561609 doi:10.1038/nsmb.1632
  3. ↑ Bosanac I, Maun HR, Scales SJ, Wen X, Lingel A, Bazan JF, de Sauvage FJ, Hymowitz SG, Lazarus RA. 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. Epub 2009 Jun 28. PMID:19561609 doi:10.1038/nsmb.1632

3ho5, resolution 3.01Å

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