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Entry version 222 (13 Nov 2019)
Sequence version 1 (01 Nov 1996)
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Protein

Sonic hedgehog protein

Gene

SHH

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the ‘protein existence’ evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Sonic hedgehog protein: The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN (By similarity). Both activities occur in the reticulum endoplasmic (By similarity). Once cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).By similarity
Sonic hedgehog protein N-product: The dually lipidated sonic hedgehog protein N-product (ShhNp) is a morphogen which is essential for a variety of patterning events during development. Induces ventral cell fate in the neural tube and somites (PubMed:24863049). Involved in the patterning of the anterior-posterior axis of the developing limb bud (By similarity). Essential for axon guidance (By similarity). Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes (PubMed:10753901). In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (PubMed:10753901).1 PublicationBy similarity2 Publications

Caution

The several steps and mechanisms that permit controlled Shh dispersion and gradient formation remain controversial. The ShhNC C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity resulting in the cleavage and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (ShhN). The protein is further modified by covalent addition of palmitate at the N-terminal of ShhN, resulting to the dual-lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane where it forms multimers. Further solubilization and release from the cell surface seem to be achieved through different mechanisms, including the interaction with DISP1 and SCUBE2, movement by lipoprotein particles, transport by cellular extensions called cytonemes or by proteolytic removal of both terminal lipidated peptides (PubMed:26875496). Once released, the fully processed Shh can signal within embryonic tissues both at short and long-range.1 Publication2 Publications1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section indicates at which position the protein binds a given metal ion. The nature of the metal is indicated in the ‘Description’ field.<p><a href='/help/metal' target='_top'>More...</a></p>Metal bindingi89Calcium 1Combined sources1 Publication1
Metal bindingi90Calcium 1Combined sources1 Publication1
Metal bindingi90Calcium 2Combined sources1 Publication1
Metal bindingi95Calcium 1Combined sources1 Publication1
Metal bindingi125Calcium 1; via carbonyl oxygenCombined sources1 Publication1
Metal bindingi126Calcium 1Combined sources1 Publication1
Metal bindingi126Calcium 2Combined sources1 Publication1
Metal bindingi129Calcium 2Combined sources1 Publication1
Metal bindingi131Calcium 2Combined sources1 Publication1
Metal bindingi140ZincCombined sources2 Publications1
Metal bindingi147ZincCombined sources2 Publications1
Metal bindingi182ZincCombined sources2 Publications1
<p>This subsection describes interesting single amino acid sites on the sequence that are not defined in any other subsection. This subsection can be displayed in different sections (‘Function’, ‘PTM / Processing’, ‘Pathology and Biotech’) according to its content.<p><a href='/help/site' target='_top'>More...</a></p>Sitei243Involved in cholesterol transferBy similarity1
Sitei267Involved in auto-cleavageBy similarity1
Sitei270Essential for auto-cleavageBy similarity1

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionDevelopmental protein, Hydrolase, Protease
LigandCalcium, Metal-binding, Zinc

Enzyme and pathway databases

Reactome - a knowledgebase of biological pathways and processes

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Reactomei
R-HSA-373080 Class B/2 (Secretin family receptors)
R-HSA-5358346 Hedgehog ligand biogenesis
R-HSA-5362768 Hh mutants that don't undergo autocatalytic processing are degraded by ERAD
R-HSA-5362798 Release of Hh-Np from the secreting cell
R-HSA-5632681 Ligand-receptor interactions
R-HSA-5632684 Hedgehog 'on' state
R-HSA-5635838 Activation of SMO
R-HSA-5658034 HHAT G278V abrogates palmitoylation of Hh-Np

SignaLink: a signaling pathway resource with multi-layered regulatory networks

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SignaLinki
Q15465

SIGNOR Signaling Network Open Resource

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SIGNORi
Q15465

Protein family/group databases

MEROPS protease database

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MEROPSi
C46.002

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
Sonic hedgehog protein
Short name:
SHH
Alternative name(s):
HHG-1
Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains1 Publication
Short name:
ShhNC1 Publication
Cleaved into the following chain:
Alternative name(s):
Shh N-terminal processed signaling domains1 Publication
Short name:
ShhNp1 Publication
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: ‘Name’, ‘Synonyms’, ‘Ordered locus names’ and ‘ORF names’.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:SHHImported
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the ‘taxonomic identifier’ or ‘taxid’.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components. <br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome 7

Organism-specific databases

Human Gene Nomenclature Database

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HGNCi
HGNC:10848 SHH

Online Mendelian Inheritance in Man (OMIM)

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MIMi
600725 gene

neXtProt; the human protein knowledge platform

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neXtProti
NX_Q15465

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte & Seán O’Donoghue; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Membrane

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

<p>This subsection of the ‘Pathology and Biotech’ section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei

Microphthalmia, isolated, with coloboma, 5 (MCOPCB5)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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, and other abnormalities 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).
Related information in OMIM
Holoprosencephaly 3 (HPE3)12 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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 holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described.
Related information in OMIM
Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Sequence’ section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_0238046R → T in HPE3. 2 Publications1
Natural variantiVAR_06259217L → P in HPE3. 1 Publication1
Natural variantiVAR_06259326P → L in HPE3. 1 Publication1
Natural variantiVAR_03988827G → A in HPE3. 2 Publications1
Natural variantiVAR_00361931G → R in HPE3; the same mutation in the mouse sequence introduces a cleavage site for a furin-like protease resulting in abnormal protein processing; cleavage at this site removes 11 amino acids from the N-terminal domain and reduces affinity of Shh for Ptch1 and signaling potency in assays using chicken embryo neural plate explants and mouse C3H10T1/2 stem cells. 4 PublicationsCorresponds to variant dbSNP:rs28936675EnsemblClinVar.1
Natural variantiVAR_06259439L → P in HPE3. 1 PublicationCorresponds to variant dbSNP:rs1428916820Ensembl.1
Natural variantiVAR_06259553E → K in HPE3. 1 Publication1
Natural variantiVAR_06259683D → V in HPE3. 1 Publication1
Natural variantiVAR_06259784I → F in HPE3. 1 Publication1
Natural variantiVAR_00916388D → V in HPE3; familial; the same mutation in the mouse sequence moderately reduces Ptch1 binding in vitro and signaling potency in chicken embryo neural plate explant assays compared with wild-type sequence. 3 PublicationsCorresponds to variant dbSNP:rs104894050EnsemblClinVar.1
Natural variantiVAR_009164100Q → H in HPE3; sporadic; in the mouse sequence does not affect signaling activity in any of Shh signaling assays and causes no apparent defects in cholesterol-mediated autoprocessing reactions. 4 PublicationsCorresponds to variant dbSNP:rs587778792EnsemblClinVar.1
Natural variantiVAR_062598102C → R in HPE3. 1 Publication1
Natural variantiVAR_062599102C → Y in HPE3. 1 Publication1
Natural variantiVAR_023805106 – 107Missing in HPE3. 2 Publications2
Natural variantiVAR_062600109L → F in HPE3. 1 Publication1
Natural variantiVAR_023806110A → D in HPE3. 2 Publications1
Natural variantiVAR_062601110A → T in HPE3. 1 Publication1
Natural variantiVAR_039889111I → N in HPE3. 2 Publications1
Natural variantiVAR_009165115N → K in HPE3; familial; in the mouse sequence shows no change in activities at different temperatures. 3 PublicationsCorresponds to variant dbSNP:rs267607047EnsemblClinVar.1
Natural variantiVAR_003620117W → G in HPE3; the same mutation in the mouse sequence causes a failure of Shh processing leading to retention of the immature glycosylated protein within the endoplasmic reticulum of transfected cells; causes a temperature-dependent conformational change that allows Shh to bind Ptch1 at 4 or 32 degrees Celsius but not at 37 degrees Celsius; the mutation drastically reduces signaling potency in chicken embryo neural plate explant assays. 4 PublicationsCorresponds to variant dbSNP:rs104894040EnsemblClinVar.1
Natural variantiVAR_003621117W → R in HPE3; the same mutation in the mouse sequence causes a failure of Shh processing leading to retention of the immature glycosylated protein within the endoplasmic reticulum of transfected cells; causes a temperature-dependent conformational change that allows Shh to bind Ptch1 at 4 or 32 degrees Celsius but not at 37 degrees Celsius; drastically reduces signaling potency in chicken embryo neural plate explant assays. 4 PublicationsCorresponds to variant dbSNP:rs104894040EnsemblClinVar.1
Natural variantiVAR_062602124V → M in HPE3. 1 Publication1
Natural variantiVAR_062603136E → K in HPE3. 1 Publication1
Natural variantiVAR_039890140H → P in HPE3. 2 Publications1
Natural variantiVAR_039891140H → Q in HPE3. 3 Publications1
Natural variantiVAR_062604143G → D in HPE3. 1 Publication1
Natural variantiVAR_062605144R → P in HPE3. 1 Publication1
Natural variantiVAR_062606147D → N in HPE3. 1 Publication1
Natural variantiVAR_062607150T → K in HPE3. 1 Publication1
Natural variantiVAR_023807150T → R in HPE3. 2 Publications1
Natural variantiVAR_062608156S → R in HPE3. 1 PublicationCorresponds to variant dbSNP:rs1554494372EnsemblClinVar.1
Natural variantiVAR_062609170F → C in HPE3. 1 Publication1
Natural variantiVAR_062610171D → H in HPE3. 1 Publication1
Natural variantiVAR_023808176 – 178Missing in HPE3. 2 Publications3
Natural variantiVAR_039892183C → F in HPE3. 2 Publications1
Natural variantiVAR_062611183C → R in HPE3. 1 Publication1
Natural variantiVAR_062612183C → Y in HPE3. 1 Publication1
Natural variantiVAR_062613184S → L in HPE3. 1 Publication1
Natural variantiVAR_009166188E → Q in HPE3; familial. 4 PublicationsCorresponds to variant dbSNP:rs587778799EnsemblClinVar.1
Natural variantiVAR_062614196 – 200Missing in HPE3. 1 Publication5
Natural variantiVAR_062615196G → E in HPE3. 1 PublicationCorresponds to variant dbSNP:rs752650571Ensembl.1
Natural variantiVAR_062616197G → V in HPE3. 1 Publication1
Natural variantiVAR_062617198C → F in HPE3. 1 Publication1
Natural variantiVAR_062618198C → S in HPE3. 1 Publication1
Natural variantiVAR_062619218L → P in HPE3. 2 Publications1
Natural variantiVAR_009167222D → N in HPE3; familial. 3 PublicationsCorresponds to variant dbSNP:rs587778805EnsemblClinVar.1
Natural variantiVAR_009168224V → E in HPE3. 2 PublicationsCorresponds to variant dbSNP:rs104894042EnsemblClinVar.1
Natural variantiVAR_009169226A → T in HPE3; familial. 2 PublicationsCorresponds to variant dbSNP:rs104894043EnsemblClinVar.1
Natural variantiVAR_062620231G → V in HPE3. 1 Publication1
Natural variantiVAR_062621232R → G in HPE3. 1 PublicationCorresponds to variant dbSNP:rs1347054935Ensembl.1
Natural variantiVAR_062622234L → P in HPE3. 1 Publication1
Natural variantiVAR_062623236S → N in HPE3. 1 Publication1
Natural variantiVAR_009170236S → R in HPE3; familial. 2 PublicationsCorresponds to variant dbSNP:rs587778806EnsemblClinVar.1
Natural variantiVAR_062624241F → L in HPE3. 1 Publication1
Natural variantiVAR_062625241F → V in HPE3. 1 Publication1
Natural variantiVAR_062626255I → N in HPE3. 1 Publication1
Natural variantiVAR_009171263 – 269Missing in HPE3; sporadic. 2 Publications7
Natural variantiVAR_039893267T → I in HPE3. 2 Publications1
Natural variantiVAR_023809271L → P in HPE3. 2 Publications1
Natural variantiVAR_062627275A → E in HPE3. 1 PublicationCorresponds to variant dbSNP:rs556192490Ensembl.1
Natural variantiVAR_062628280S → W in HPE3. 1 Publication1
Natural variantiVAR_009172290G → D in HPE3; sporadic. 2 PublicationsCorresponds to variant dbSNP:rs104894047EnsemblClinVar.1
Natural variantiVAR_062629296G → A in HPE3; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs955894039Ensembl.1
Natural variantiVAR_062630310R → C in HPE3. 1 Publication1
Natural variantiVAR_062631321R → S in HPE3. 1 Publication1
Natural variantiVAR_023810332V → A in HPE3 and SMMCI. 3 PublicationsCorresponds to variant dbSNP:rs104894052EnsemblClinVar.1
Natural variantiVAR_062632346A → V in HPE3. 1 Publication1
Natural variantiVAR_062633347P → L in HPE3. 1 Publication1
Natural variantiVAR_023811347P → Q in HPE3. 2 Publications1
Natural variantiVAR_062634347P → R in HPE3. 1 PublicationCorresponds to variant dbSNP:rs886042458EnsemblClinVar.1
Natural variantiVAR_023812354I → T in HPE3. 2 Publications1
Natural variantiVAR_062635362S → L in HPE3. 1 Publication1
Natural variantiVAR_062636363C → Y in HPE3. 2 Publications1
Natural variantiVAR_062637364Y → C in HPE3. 1 Publication1
Natural variantiVAR_039894373A → T in HPE3. 2 Publications1
Natural variantiVAR_062638374H → R in HPE3. 1 Publication1
Natural variantiVAR_062639376A → D in HPE3. 1 Publication1
Natural variantiVAR_062640377F → S in HPE3. 1 Publication1
Natural variantiVAR_009173378 – 380Missing in HPE3; familial. 1 Publication3
Natural variantiVAR_023813381R → P in HPE3. 2 Publications1
Natural variantiVAR_062641382L → P in HPE3. 1 Publication1
Natural variantiVAR_009174383A → T in HPE3; sporadic. 2 PublicationsCorresponds to variant dbSNP:rs137853341EnsemblClinVar.1
Natural variantiVAR_062642391A → T in HPE3; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs1131692264EnsemblClinVar.1
Natural variantiVAR_062643402 – 409Missing in HPE3; unknown pathological significance. 1 Publication8
Natural variantiVAR_009175404 – 408Missing in HPE3; familial. 5
Natural variantiVAR_062644405 – 409Missing in HPE3; unknown pathological significance. 1 Publication5
Natural variantiVAR_062645411G → GG in HPE3; unknown pathological significance. 1 Publication1
Natural variantiVAR_062646416T → A in HPE3; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs1412744230Ensembl.1
Natural variantiVAR_009176424P → A in HPE3; familial. 2 PublicationsCorresponds to variant dbSNP:rs104894048EnsemblClinVar.1
Natural variantiVAR_062647435Y → N in HPE3. 1 Publication1
Natural variantiVAR_009177436S → L in HPE3; sporadic. 2 Publications1
Natural variantiVAR_062648456G → R in HPE3; unknown pathological significance. 1 Publication1
Solitary median maxillary central incisor (SMMCI)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRare dental anomaly characterized by the congenital absence of one maxillary central incisor.
Related information in OMIM
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_017883111I → F in SMMCI. 2 PublicationsCorresponds to variant dbSNP:rs104894049EnsemblClinVar.1
Natural variantiVAR_023810332V → A in HPE3 and SMMCI. 3 PublicationsCorresponds to variant dbSNP:rs104894052EnsemblClinVar.1
Triphalangeal thumb-polysyndactyly syndrome (TPTPS)2 Publications
The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression.
Disease descriptionAutosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development.
Related information in OMIM
Preaxial polydactyly 2 (PPD2)1 Publication
The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695).1 Publication
Disease descriptionPolydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal.
Related information in OMIM
Hypoplasia or aplasia of tibia with polydactyly (THYP)2 Publications
The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences.2 Publications
Disease descriptionAn autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly.
Related information in OMIM
Laurin-Sandrow syndrome (LSS)1 Publication
The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159).
Disease descriptionA rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome).
Related information in OMIM

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi24C → S: Abolishes palmitoylation. 1 Publication1

Keywords - Diseasei

Disease mutation, Holoprosencephaly, Microphthalmia

Organism-specific databases

DisGeNET

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DisGeNETi
6469

GeneReviews a resource of expert-authored, peer-reviewed disease descriptions.

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GeneReviewsi
SHH

MalaCards human disease database

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MalaCardsi
SHH
MIMi135750 phenotype
142945 phenotype
147250 phenotype
174500 phenotype
188740 phenotype
611638 phenotype

Open Targets

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OpenTargetsi
ENSG00000164690

Orphanet; a database dedicated to information on rare diseases and orphan drugs

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Orphaneti
485275 Acquired schizencephaly
93925 Alobar holoprosencephaly
476119 Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
98938 Colobomatous microphthalmia
3332 Hypoplastic tibiae-postaxial polydactyly syndrome
93924 Lobar holoprosencephaly
280200 Microform holoprosencephaly
93926 Midline interhemispheric variant of holoprosencephaly
93336 Polydactyly of a triphalangeal thumb
93321 Radial hemimelia
220386 Semilobar holoprosencephaly
280195 Septopreoptic holoprosencephaly
93405 Syndactyly type 4
2950 Triphalangeal thumb-polysyndactyly syndrome

The Pharmacogenetics and Pharmacogenomics Knowledge Base

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PharmGKBi
PA35752

Miscellaneous databases

Pharos NIH Druggable Genome Knowledgebase

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Pharosi
Q15465

Chemistry databases

ChEMBL database of bioactive drug-like small molecules

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ChEMBLi
CHEMBL5602

DrugCentral

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DrugCentrali
Q15465

Polymorphism and mutation databases

BioMuta curated single-nucleotide variation and disease association database

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BioMutai
SHH

Domain mapping of disease mutations (DMDM)

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DMDMi
6094283

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘PTM / Processing’ section denotes the presence of an N-terminal signal peptide.<p><a href='/help/signal' target='_top'>More...</a></p>Signal peptidei1 – 231 PublicationAdd BLAST23
<p>This subsection of the ‘PTM / Processing’ section describes the extent of a polypeptide chain in the mature protein following processing.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_000001320824 – 462Sonic hedgehog proteinAdd BLAST439
ChainiPRO_000001320924 – 197Sonic hedgehog protein N-productAdd BLAST174

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section specifies the position(s) and the type of covalently attached lipid group(s).<p><a href='/help/lipid' target='_top'>More...</a></p>Lipidationi24N-palmitoyl cysteine1 Publication1
Lipidationi197Cholesterol glycine esterBy similarity1
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section specifies the position and type of each covalently attached glycan group (mono-, di-, or polysaccharide).<p><a href='/help/carbohyd' target='_top'>More...</a></p>Glycosylationi278N-linked (GlcNAc...) asparagine1 Publication1

<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>Post-translational modificationi

Sonic hedgehog protein: The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (ShhN) (By similarity). Cholesterylation is required for the sonic hedgehog protein N-product targeting to lipid rafts and multimerization (PubMed:24522195, PubMed:26875496). ShhN is the active species in both local and long-range signaling, whereas the C-product (ShhC) is degraded in the reticulum endoplasmic (By similarity).1 PublicationBy similarity1 Publication
Sonic hedgehog protein N-product: N-palmitoylation by HHAT of ShhN is required for sonic hedgehog protein N-product multimerization and full activity (By similarity). It is a prerequisite for the membrane-proximal positioning and the subsequent shedding of this N-terminal peptide (PubMed:24522195).By similarity1 Publication
Sonic hedgehog protein N-product: The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding)(PubMed:24522195). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195, PubMed:23118222).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei197 – 198Cleavage; by autolysisBy similarity2

Keywords - PTMi

Autocatalytic cleavage, Glycoprotein, Lipoprotein, Palmitate

Proteomic databases

MassIVE - Mass Spectrometry Interactive Virtual Environment

More...
MassIVEi
Q15465

PaxDb, a database of protein abundance averages across all three domains of life

More...
PaxDbi
Q15465

PeptideAtlas

More...
PeptideAtlasi
Q15465

PRoteomics IDEntifications database

More...
PRIDEi
Q15465

ProteomicsDB: a multi-organism proteome resource

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ProteomicsDBi
60602

PTM databases

iPTMnet integrated resource for PTMs in systems biology context

More...
iPTMneti
Q15465

Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.

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PhosphoSitePlusi
Q15465

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

Gene expression databases

Bgee dataBase for Gene Expression Evolution

More...
Bgeei
ENSG00000164690 Expressed in 102 organ(s), highest expression level in left adrenal gland

ExpressionAtlas, Differential and Baseline Expression

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ExpressionAtlasi
Q15465 baseline and differential

Genevisible search portal to normalized and curated expression data from Genevestigator

More...
Genevisiblei
Q15465 HS

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

<p>This subsection of the <a href="http://www.uniprot.org/help/interaction_section">'Interaction'</a> section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section).<p><a href='/help/subunit_structure' target='_top'>More...</a></p>Subunit structurei

Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus (By similarity). ShhNp is active as a multimer (PubMed:24522195).

Interacts with BOC and CDON (By similarity).

Interacts with HHIP (PubMed:19561609).

Interacts with DISP1 via its cholesterol anchor (PubMed:22902404, PubMed:22677548).

Interacts with SCUBE2 (PubMed:24522195, PubMed:22677548).

Interacts with glypican GPC3 (By similarity).

By similarity4 Publications

<p>This subsection of the '<a href="http://www.uniprot.org/help/interaction_section%27">Interaction</a> section provides information about binary protein-protein interactions. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the <a href="http://www.ebi.ac.uk/intact/">IntAct database</a>. It is updated on a monthly basis. Each binary interaction is displayed on a separate line.<p><a href='/help/binary_interactions' target='_top'>More...</a></p>Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

The Biological General Repository for Interaction Datasets (BioGrid)

More...
BioGridi
112365, 8 interactors

Database of interacting proteins

More...
DIPi
DIP-61763N

Protein interaction database and analysis system

More...
IntActi
Q15465, 3 interactors

STRING: functional protein association networks

More...
STRINGi
9606.ENSP00000297261

Chemistry databases

BindingDB database of measured binding affinities

More...
BindingDBi
Q15465

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

Secondary structure

1462
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

SWISS-MODEL Repository - a database of annotated 3D protein structure models

More...
SMRi
Q15465

Database of comparative protein structure models

More...
ModBasei
Search...

Protein Data Bank in Europe - Knowledge Base

More...
PDBe-KBi
Search...

Miscellaneous databases

Relative evolutionary importance of amino acids within a protein sequence

More...
EvolutionaryTracei
Q15465

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Family and Domains’ section describes a short (usually not more than 20 amino acids) conserved sequence motif of biological significance.<p><a href='/help/motif' target='_top'>More...</a></p>Motifi32 – 38Cardin-Weintraub1 Publication7

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the ‘Family and Domains’ section describes the position of regions of compositional bias within the protein and the particular amino acids that are over-represented within those regions.<p><a href='/help/compbias' target='_top'>More...</a></p>Compositional biasi407 – 411Poly-Gly5

<p>This subsection of the ‘Family and domains’ section provides general information on the biological role of a domain. The term ‘domain’ is intended here in its wide acceptation, it may be a structural domain, a transmembrane region or a functional domain. Several domains are described in this subsection.<p><a href='/help/domain_cc' target='_top'>More...</a></p>Domaini

Sonic hedgehog protein N-product: Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.3 Publications
Sonic hedgehog protein N-product: The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized ShhNp (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at the heparan sulfate-binding Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).2 Publications

<p>This subsection of the ‘Family and domains’ section provides information about the sequence similarity with other proteins.<p><a href='/help/sequence_similarities' target='_top'>More...</a></p>Sequence similaritiesi

Belongs to the hedgehog family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

evolutionary genealogy of genes: Non-supervised Orthologous Groups

More...
eggNOGi
KOG3638 Eukaryota
ENOG410XQA3 LUCA

Ensembl GeneTree

More...
GeneTreei
ENSGT00940000159119

The HOGENOM Database of Homologous Genes from Fully Sequenced Organisms

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HOGENOMi
HOG000233428

InParanoid: Eukaryotic Ortholog Groups

More...
InParanoidi
Q15465

KEGG Orthology (KO)

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KOi
K11988

Identification of Orthologs from Complete Genome Data

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OMAi
YAVIEDH

Database of Orthologous Groups

More...
OrthoDBi
1169356at2759

Database for complete collections of gene phylogenies

More...
PhylomeDBi
Q15465

TreeFam database of animal gene trees

More...
TreeFami
TF106458

Family and domain databases

Gene3D Structural and Functional Annotation of Protein Families

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Gene3Di
3.30.1380.10, 1 hit

Integrated resource of protein families, domains and functional sites

More...
InterProi
View protein in InterPro
IPR001657 Hedgehog
IPR001767 Hedgehog_Hint
IPR009045 Hedgehog_sig/DD-Pept_Zn-bd_sf
IPR000320 Hedgehog_signalling_dom
IPR003586 Hint_dom_C
IPR003587 Hint_dom_N
IPR036844 Hint_dom_sf
IPR006141 Intein_N

Pfam protein domain database

More...
Pfami
View protein in Pfam
PF01085 HH_signal, 1 hit
PF01079 Hint, 1 hit

PIRSF; a whole-protein classification database

More...
PIRSFi
PIRSF009400 Peptidase_C46, 1 hit

Protein Motif fingerprint database; a protein domain database

More...
PRINTSi
PR00632 SONICHHOG

Simple Modular Architecture Research Tool; a protein domain database

More...
SMARTi
View protein in SMART
SM00305 HintC, 1 hit
SM00306 HintN, 1 hit

Superfamily database of structural and functional annotation

More...
SUPFAMi
SSF51294 SSF51294, 1 hit
SSF55166 SSF55166, 1 hit

PROSITE; a protein domain and family database

More...
PROSITEi
View protein in PROSITE
PS50817 INTEIN_N_TER, 1 hit

<p>This section displays by default the canonical protein sequence and upon request all isoforms described in the entry. It also includes information pertinent to the sequence(s), including <a href="http://www.uniprot.org/help/sequence_length">length</a> and <a href="http://www.uniprot.org/help/sequences">molecular weight</a>. The information is filed in different subsections. The current subsections and their content are listed below:<p><a href='/help/sequences_section' target='_top'>More...</a></p>Sequence (1+)i

<p>This subsection of the <a href="http://www.uniprot.org/help/sequences_section">Sequence</a> section indicates if the <a href="http://www.uniprot.org/help/canonical_and_isoforms">canonical sequence</a> displayed by default in the entry is complete or not.<p><a href='/help/sequence_status' target='_top'>More...</a></p>Sequence statusi: Complete.

<p>This subsection of the <a href="http://www.uniprot.org/help/sequences_section">Sequence</a> section indicates if the <a href="http://www.uniprot.org/help/canonical_and_isoforms">canonical sequence</a> displayed by default in the entry is in its mature form or if it represents the precursor.<p><a href='/help/sequence_processing' target='_top'>More...</a></p>Sequence processingi: The displayed sequence is further processed into a mature form.

This entry has 1 described isoform and 3 potential isoforms that are computationally mapped.Show allAlign All

Q15465-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN
60 70 80 90 100
VAEKTLGASG RYEGKISRNS ERFKELTPNY NPDIIFKDEE NTGADRLMTQ
110 120 130 140 150
RCKDKLNALA ISVMNQWPGV KLRVTEGWDE DGHHSEESLH YEGRAVDITT
160 170 180 190 200
SDRDRSKYGM LARLAVEAGF DWVYYESKAH IHCSVKAENS VAAKSGGCFP
210 220 230 240 250
GSATVHLEQG GTKLVKDLSP GDRVLAADDQ GRLLYSDFLT FLDRDDGAKK
260 270 280 290 300
VFYVIETREP RERLLLTAAH LLFVAPHNDS ATGEPEASSG SGPPSGGALG
310 320 330 340 350
PRALFASRVR PGQRVYVVAE RDGDRRLLPA AVHSVTLSEE AAGAYAPLTA
360 370 380 390 400
QGTILINRVL ASCYAVIEEH SWAHRAFAPF RLAHALLAAL APARTDRGGD
410 420 430 440 450
SGGGDRGGGG GRVALTAPGA ADAPGAGATA GIHWYSQLLY QIGTWLLDSE
460
ALHPLGMAVK SS
Length:462
Mass (Da):49,607
Last modified:November 1, 1996 - v1
<p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.</p> <p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.</p> <p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).</p> <p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x<sup>64</sup> + x<sup>4</sup> + x<sup>3</sup> + x + 1. The algorithm is described in the ISO 3309 standard. </p> <p class="publication">Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.<br /> <strong>Cyclic redundancy and other checksums</strong><br /> <a href="http://www.nrbook.com/b/bookcpdf.php">Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993)</a>)</p> Checksum:iDD687AFA582A4749
GO

<p>In eukaryotic reference proteomes, unreviewed entries that are likely to belong to the same gene are computationally mapped, based on gene identifiers from Ensembl, EnsemblGenomes and model organism databases.<p><a href='/help/gene_centric_isoform_mapping' target='_top'>More...</a></p>Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
C9JC48C9JC48_HUMAN
Sonic hedgehog protein
SHH
169Annotation score:

Annotation score:1 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
F8WB84F8WB84_HUMAN
Sonic hedgehog protein
SHH
126Annotation score:

Annotation score:1 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
F8WEH4F8WEH4_HUMAN
Sonic hedgehog protein
SHH
123Annotation score:

Annotation score:1 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the ‘correct annotation’ for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>

<p>This subsection of the ‘Sequence’ section reports information derived from mass spectrometry experiments done on the entire protein or on biologically active derived peptide(s).<p><a href='/help/mass_spectrometry' target='_top'>More...</a></p>Mass spectrometryi

Molecular mass is 19.560 Da from positions 24 - 197. Determined by ESI. Sonic hedgehog protein N-product: soluble product, purified from insect cells.1 Publication
Molecular mass is 20.167 Da from positions 24 - 197. Determined by ESI. Sonic hedgehog protein N-product: Membrane-bound product, purified from insect cells.1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0238046R → T in HPE3. 2 Publications1
Natural variantiVAR_06259217L → P in HPE3. 1 Publication1
Natural variantiVAR_06259326P → L in HPE3. 1 Publication1
Natural variantiVAR_03988827G → A in HPE3. 2 Publications1
Natural variantiVAR_00361931G → R in HPE3; the same mutation in the mouse sequence introduces a cleavage site for a furin-like protease resulting in abnormal protein processing; cleavage at this site removes 11 amino acids from the N-terminal domain and reduces affinity of Shh for Ptch1 and signaling potency in assays using chicken embryo neural plate explants and mouse C3H10T1/2 stem cells. 4 PublicationsCorresponds to variant dbSNP:rs28936675EnsemblClinVar.1
Natural variantiVAR_06259439L → P in HPE3. 1 PublicationCorresponds to variant dbSNP:rs1428916820Ensembl.1
Natural variantiVAR_06259553E → K in HPE3. 1 Publication1
Natural variantiVAR_06259683D → V in HPE3. 1 Publication1
Natural variantiVAR_06259784I → F in HPE3. 1 Publication1
Natural variantiVAR_00916388D → V in HPE3; familial; the same mutation in the mouse sequence moderately reduces Ptch1 binding in vitro and signaling potency in chicken embryo neural plate explant assays compared with wild-type sequence. 3 PublicationsCorresponds to variant dbSNP:rs104894050EnsemblClinVar.1
Natural variantiVAR_009164100Q → H in HPE3; sporadic; in the mouse sequence does not affect signaling activity in any of Shh signaling assays and causes no apparent defects in cholesterol-mediated autoprocessing reactions. 4 Publications