| Structural highlights
Disease
[SHH_HUMAN] Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM: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).[1] Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:142945]. Holoprosencephaly (HPE) [MIM: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.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:147250]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.[14] [15] Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM: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.[16]
Function
[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).
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
Proper hedgehog (Hh) signaling is crucial for embryogenesis and tissue regeneration. Dysregulation of this pathway is associated with several types of cancer. The monoclonal antibody 5E1 is a Hh pathway inhibitor that has been extensively used to elucidate vertebrate Hh biology due to its ability to block binding of the three mammalian Hh homologs to the receptor, Patched1 (Ptc1). Here, we engineered a murine:human chimeric 5E1 (ch5E1) with similar Hh-binding properties to the original murine antibody. Using biochemical, biophysical, and x-ray crystallographic studies, we show that, like the regulatory receptors Cdon and Hedgehog-interacting protein (Hhip), ch5E1 binding to Sonic hedgehog (Shh) is enhanced by calcium ions. In the presence of calcium and zinc ions, the ch5E1 binding affinity increases 10-20-fold to tighter than 1 nm primarily because of a decrease in the dissociation rate. The co-crystal structure of Shh bound to the Fab fragment of ch5E1 reveals that 5E1 binds at the pseudo-active site groove of Shh with an epitope that largely overlaps with the binding site of its natural receptor antagonist Hhip. Unlike Hhip, the side chains of 5E1 do not directly coordinate the Zn(2+) cation in the pseudo-active site, despite the modest zinc-dependent increase in 5E1 affinity for Shh. Furthermore, to our knowledge, the ch5E1 Fab-Shh complex represents the first structure of an inhibitor antibody bound to a metalloprotease fold.
Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site.,Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, Scales SJ, Hymowitz SG J Biol Chem. 2010 Aug 20;285(34):26570-80. Epub 2010 May 26. PMID:20504762[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schimmenti LA, de la Cruz J, Lewis RA, Karkera JD, Manligas GS, Roessler E, Muenke M. Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia. Am J Med Genet A. 2003 Jan 30;116A(3):215-21. PMID:12503095 doi:10.1002/ajmg.a.10884
- ↑ Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996 Nov;14(3):357-60. PMID:8896572 doi:10.1038/ng1196-357
- ↑ Roessler E, Belloni E, Gaudenz K, Vargas F, Scherer SW, Tsui LC, Muenke M. Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum Mol Genet. 1997 Oct;6(11):1847-53. PMID:9302262
- ↑ Odent S, Atti-Bitach T, Blayau M, Mathieu M, Aug J, Delezo de AL, Gall JY, Le Marec B, Munnich A, David V, Vekemans M. Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum Mol Genet. 1999 Sep;8(9):1683-9. PMID:10441331
- ↑ Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet. 1999 Dec;8(13):2479-88. PMID:10556296
- ↑ Orioli IM, Castilla EE, Ming JE, Nazer J, Burle de Aguiar MJ, Llerena JC, Muenke M. Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Hum Genet. 2001 Jul;109(1):1-6. PMID:11479728
- ↑ Hehr U, Gross C, Diebold U, Wahl D, Beudt U, Heidemann P, Hehr A, Mueller D. Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation. Eur J Pediatr. 2004 Jul;163(7):347-52. Epub 2004 Apr 24. PMID:15107988 doi:10.1007/s00431-004-1459-0
- ↑ Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le Duff F, Durou MR, Odent S, David V. Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. Hum Mutat. 2004 Jul;24(1):43-51. PMID:15221788 doi:10.1002/humu.20056
- ↑ El-Jaick KB, Brunoni D, Castilla EE, Moreira MA, Orioli IM. SHH Ile111Asp in alobar holoprosencephaly in a proposita, whose mother had only a solitary median maxillary incisor. Am J Med Genet A. 2005 Aug 1;136A(4):345. PMID:15942952 doi:10.1002/ajmg.a.30624
- ↑ Ribeiro LA, Richieri-Costa A. Single median maxillary central incisor, hypophyseal tumor, and SHH mutation. Am J Med Genet A. 2005 Aug 1;136A(4):346-7. PMID:15942953 doi:10.1002/ajmg.a.30625
- ↑ Maity T, Fuse N, Beachy PA. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17026-31. Epub 2005 Nov 10. PMID:16282375 doi:10.1073/pnas.0507848102
- ↑ Richieri-Costa A, Ribeiro LA. Holoprosencephaly-like phenotype: clinical and genetic perspectives. Am J Med Genet A. 2006 Dec 1;140(23):2587-93. PMID:17001669 doi:10.1002/ajmg.a.31378
- ↑ Roessler E, El-Jaick KB, Dubourg C, Velez JI, Solomon BD, Pineda-Alvarez DE, Lacbawan F, Zhou N, Ouspenskaia M, Paulussen A, Smeets HJ, Hehr U, Bendavid C, Bale S, Odent S, David V, Muenke M. The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis. Hum Mutat. 2009 Oct;30(10):E921-35. doi: 10.1002/humu.21090. PMID:19603532 doi:10.1002/humu.21090
- ↑ Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M. SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. Am J Med Genet. 2001 Jul 22;102(1):1-10. PMID:11471164
- ↑ Garavelli L, Zanacca C, Caselli G, Banchini G, Dubourg C, David V, Odent S, Gurrieri F, Neri G. Solitary median maxillary central incisor syndrome: clinical case with a novel mutation of sonic hedgehog. Am J Med Genet A. 2004 May 15;127A(1):93-5. PMID:15103725 doi:10.1002/ajmg.a.20685
- ↑ Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, Goode D, Elgar G, Hill RE, de Graaff E. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 2003 Jul 15;12(14):1725-35. PMID:12837695
- ↑ Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, Scales SJ, Hymowitz SG. Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site. J Biol Chem. 2010 Aug 20;285(34):26570-80. Epub 2010 May 26. PMID:20504762 doi:10.1074/jbc.M110.112284
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