2wfx is a 2 chain structure with sequence from Human and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[SHH_MOUSE] 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).[1] [HHIP_HUMAN] Modulates hedgehog signaling in several cell types including brain and lung through direct interaction with members of the hedgehog family.[2][3]
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) 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.
Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.,Bishop B, Aricescu AR, Harlos K, O'Callaghan CA, Jones EY, Siebold C Nat Struct Mol Biol. 2009 Jul;16(7):698-703. Epub 2009 Jun 28. PMID:19561611[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Roelink H, Porter JA, Chiang C, Tanabe Y, Chang DT, Beachy PA, Jessell TM. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell. 1995 May 5;81(3):445-55. PMID:7736596
↑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
↑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
↑Bishop B, Aricescu AR, Harlos K, O'Callaghan CA, Jones EY, Siebold C. Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP. Nat Struct Mol Biol. 2009 Jul;16(7):698-703. Epub 2009 Jun 28. PMID:19561611 doi:10.1038/nsmb.1607
