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| | ==Structure of 2:1 human Ptch1-Shh-N complex== | | ==Structure of 2:1 human Ptch1-Shh-N complex== |
| - | <StructureSection load='6e1h' size='340' side='right'caption='[[6e1h]], [[Resolution|resolution]] 3.50Å' scene=''> | + | <SX load='6e1h' size='340' side='right' viewer='molstar' caption='[[6e1h]], [[Resolution|resolution]] 3.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e1h]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E1H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E1H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e1h]] 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=6E1H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E1H 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='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=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene></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=6e1h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e1h OCA], [https://pdbe.org/6e1h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e1h RCSB], [https://www.ebi.ac.uk/pdbsum/6e1h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e1h ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTCH1, PTCH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SHH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6e1h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e1h OCA], [http://pdbe.org/6e1h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e1h RCSB], [http://www.ebi.ac.uk/pdbsum/6e1h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e1h ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PTC1_HUMAN PTC1_HUMAN]] Semilobar holoprosencephaly;Monosomy 9q22.3;Alobar holoprosencephaly;Microform holoprosencephaly;Septopreoptic holoprosencephaly;Gorlin syndrome;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly. The disease may be caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [[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> | + | [https://www.uniprot.org/uniprot/PTC1_HUMAN PTC1_HUMAN] Semilobar holoprosencephaly;Monosomy 9q22.3;Alobar holoprosencephaly;Microform holoprosencephaly;Septopreoptic holoprosencephaly;Gorlin syndrome;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly. The disease may be caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PTC1_HUMAN PTC1_HUMAN]] Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.<ref>PMID:21537345</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/PTC1_HUMAN PTC1_HUMAN] Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.<ref>PMID:21537345</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Sonic Hedgehog|Sonic Hedgehog]] | + | *[[Protein patched homolog 1|Protein patched homolog 1]] |
| | + | *[[Sonic hedgehog 3D structures|Sonic hedgehog 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Li, X]] | + | [[Category: Li X]] |
| - | [[Category: Qi, X]] | + | [[Category: Qi X]] |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Tumor suppressor]]
| + | |
| Structural highlights
Disease
PTC1_HUMAN Semilobar holoprosencephaly;Monosomy 9q22.3;Alobar holoprosencephaly;Microform holoprosencephaly;Septopreoptic holoprosencephaly;Gorlin syndrome;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly. The disease may be caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
PTC1_HUMAN Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.[1]
Publication Abstract from PubMed
Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Here, our 3.5-A resolution cryo-EM structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.
Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex.,Qi X, Schmiege P, Coutavas E, Li X Science. 2018 Aug 23. pii: science.aas8843. doi: 10.1126/science.aas8843. PMID:30139912[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ma G, Yu J, Xiao Y, Chan D, Gao B, Hu J, He Y, Guo S, Zhou J, Zhang L, Gao L, Zhang W, Kang Y, Cheah KS, Feng G, Guo X, Wang Y, Zhou CZ, He L. Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels. Cell Res. 2011 Sep;21(9):1343-57. doi: 10.1038/cr.2011.76. Epub 2011 May 3. PMID:21537345 doi:http://dx.doi.org/10.1038/cr.2011.76
- ↑ Qi X, Schmiege P, Coutavas E, Li X. Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex. Science. 2018 Aug 23. pii: science.aas8843. doi: 10.1126/science.aas8843. PMID:30139912 doi:http://dx.doi.org/10.1126/science.aas8843
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