7pgm: Difference between revisions
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==HHIP-C in complex with heparin== | |||
<StructureSection load='7pgm' size='340' side='right'caption='[[7pgm]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7pgm]] 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=7PGM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PGM FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IDS:2-O-SULFO-ALPHA-L-IDOPYRANURONIC+ACID'>IDS</scene>, <scene name='pdbligand=SGN:N,O6-DISULFO-GLUCOSAMINE'>SGN</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=7pgm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7pgm OCA], [https://pdbe.org/7pgm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7pgm RCSB], [https://www.ebi.ac.uk/pdbsum/7pgm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7pgm ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the cholesterol moiety covalently linked to HH ligands, thereby preventing this SHH-attached cholesterol from binding to the HH receptor Patched (PTCH1). We also present the structure of the HHIP C-terminal domain in complex with the GAG heparin. Heparin can bind to both HHIP-N and HHIP-C, thereby inducing clustering at the cell surface and generating a high-avidity platform for SHH sequestration and inhibition. Our data suggest a multimodal mechanism, in which HHIP can bind two specific sites on the SHH morphogen, alongside multiple GAG interactions, to inhibit SHH signalling. | |||
Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling.,Griffiths SC, Schwab RA, El Omari K, Bishop B, Iverson EJ, Malinauskas T, Dubey R, Qian M, Covey DF, Gilbert RJC, Rohatgi R, Siebold C Nat Commun. 2021 Dec 9;12(1):7171. doi: 10.1038/s41467-021-27475-2. PMID:34887403<ref>PMID:34887403</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7pgm" style="background-color:#fffaf0;"></div> | ||
[[Category: Bishop | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Griffiths | [[Category: Large Structures]] | ||
[[Category: Iverson | [[Category: Bishop B]] | ||
[[Category: Malinuskas | [[Category: Covey DF]] | ||
[[Category: | [[Category: Dubey R]] | ||
[[Category: | [[Category: El Omari K]] | ||
[[Category: Siebold | [[Category: Gilbert RJC]] | ||
[[Category: Griffiths SC]] | |||
[[Category: Iverson EJ]] | |||
[[Category: Malinuskas T]] | |||
[[Category: Qian M]] | |||
[[Category: Rohatgi R]] | |||
[[Category: Schwab RA]] | |||
[[Category: Siebold C]] | |||
Latest revision as of 16:05, 1 February 2024
HHIP-C in complex with heparinHHIP-C in complex with heparin
Structural highlights
FunctionHHIP_HUMAN Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.[1] [2] Publication Abstract from PubMedHedgehog (HH) morphogen signalling, crucial for cell growth and tissue patterning in animals, is initiated by the binding of dually lipidated HH ligands to cell surface receptors. Hedgehog-Interacting Protein (HHIP), the only reported secreted inhibitor of Sonic Hedgehog (SHH) signalling, binds directly to SHH with high nanomolar affinity, sequestering SHH. Here, we report the structure of the HHIP N-terminal domain (HHIP-N) in complex with a glycosaminoglycan (GAG). HHIP-N displays a unique bipartite fold with a GAG-binding domain alongside a Cysteine Rich Domain (CRD). We show that HHIP-N is required to convey full HHIP inhibitory function, likely by interacting with the cholesterol moiety covalently linked to HH ligands, thereby preventing this SHH-attached cholesterol from binding to the HH receptor Patched (PTCH1). We also present the structure of the HHIP C-terminal domain in complex with the GAG heparin. Heparin can bind to both HHIP-N and HHIP-C, thereby inducing clustering at the cell surface and generating a high-avidity platform for SHH sequestration and inhibition. Our data suggest a multimodal mechanism, in which HHIP can bind two specific sites on the SHH morphogen, alongside multiple GAG interactions, to inhibit SHH signalling. Hedgehog-Interacting Protein is a multimodal antagonist of Hedgehog signalling.,Griffiths SC, Schwab RA, El Omari K, Bishop B, Iverson EJ, Malinauskas T, Dubey R, Qian M, Covey DF, Gilbert RJC, Rohatgi R, Siebold C Nat Commun. 2021 Dec 9;12(1):7171. doi: 10.1038/s41467-021-27475-2. PMID:34887403[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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