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Q15465

- SHH_HUMAN

UniProt

Q15465 - SHH_HUMAN

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Protein

Sonic hedgehog protein

Gene
SHH
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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. Activates the transcription of target genes by interacting with its receptor PTCH1 to prevent normal inhibition by PTCH1 on the constitutive signaling activity of SMO By similarity.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi89 – 891Calcium 1
Metal bindingi90 – 901Calcium 1
Metal bindingi90 – 901Calcium 2
Metal bindingi95 – 951Calcium 1
Metal bindingi125 – 1251Calcium 1; via carbonyl oxygen
Metal bindingi126 – 1261Calcium 1
Metal bindingi126 – 1261Calcium 2
Metal bindingi129 – 1291Calcium 2
Metal bindingi131 – 1311Calcium 2
Metal bindingi140 – 1401Zinc
Metal bindingi147 – 1471Zinc
Metal bindingi182 – 1821Zinc
Sitei197 – 1982Cleavage; by autolysis By similarity
Sitei243 – 2431Involved in cholesterol transfer By similarity
Sitei267 – 2671Involved in auto-cleavage By similarity
Sitei270 – 2701Essential for auto-cleavage By similarity

GO - Molecular functioni

  1. calcium ion binding Source: UniProtKB
  2. glycosaminoglycan binding Source: Ensembl
  3. laminin-1 binding Source: UniProtKB
  4. morphogen activity Source: BHF-UCL
  5. patched binding Source: BHF-UCL
  6. peptidase activity Source: UniProtKB-KW
  7. protein binding Source: UniProtKB
  8. zinc ion binding Source: UniProtKB

GO - Biological processi

  1. androgen metabolic process Source: UniProtKB
  2. apoptotic signaling pathway Source: UniProt
  3. artery development Source: Ensembl
  4. axon guidance Source: UniProtKB
  5. Bergmann glial cell differentiation Source: Ensembl
  6. blood coagulation Source: Ensembl
  7. branching involved in salivary gland morphogenesis Source: Ensembl
  8. branching involved in ureteric bud morphogenesis Source: UniProtKB
  9. branching morphogenesis of an epithelial tube Source: UniProtKB
  10. bud outgrowth involved in lung branching Source: Ensembl
  11. camera-type eye development Source: Ensembl
  12. canonical Wnt signaling pathway Source: Ensembl
  13. CD4-positive or CD8-positive, alpha-beta T cell lineage commitment Source: BHF-UCL
  14. cell-cell signaling Source: UniProtKB
  15. cell development Source: UniProtKB
  16. cell fate specification Source: UniProtKB
  17. cellular response to lithium ion Source: Ensembl
  18. central nervous system development Source: UniProtKB
  19. cerebellar granule cell precursor proliferation Source: UniProtKB
  20. determination of left/right asymmetry in lateral mesoderm Source: BHF-UCL
  21. dorsal/ventral neural tube patterning Source: Ensembl
  22. dorsal/ventral pattern formation Source: UniProtKB
  23. ectoderm development Source: Ensembl
  24. embryo development Source: UniProtKB
  25. embryonic digestive tract morphogenesis Source: Ensembl
  26. embryonic digit morphogenesis Source: UniProtKB
  27. embryonic foregut morphogenesis Source: Ensembl
  28. embryonic forelimb morphogenesis Source: Ensembl
  29. embryonic hindlimb morphogenesis Source: Ensembl
  30. embryonic limb morphogenesis Source: UniProtKB
  31. embryonic pattern specification Source: BHF-UCL
  32. embryonic skeletal system development Source: Ensembl
  33. endocytosis Source: Ensembl
  34. epithelial cell proliferation involved in salivary gland morphogenesis Source: Ensembl
  35. epithelial-mesenchymal signaling involved in prostate gland development Source: MGI
  36. establishment of cell polarity Source: Ensembl
  37. forebrain development Source: UniProtKB
  38. formation of anatomical boundary Source: Ensembl
  39. hair follicle morphogenesis Source: Ensembl
  40. heart development Source: UniProtKB
  41. heart looping Source: BHF-UCL
  42. hindbrain development Source: UniProtKB
  43. hindgut morphogenesis Source: Ensembl
  44. inner ear development Source: Ensembl
  45. intein-mediated protein splicing Source: InterPro
  46. intermediate filament organization Source: Ensembl
  47. left lung development Source: Ensembl
  48. limb bud formation Source: Ensembl
  49. lung-associated mesenchyme development Source: Ensembl
  50. lung development Source: UniProtKB
  51. lung epithelium development Source: Ensembl
  52. lung lobe morphogenesis Source: Ensembl
  53. lymphoid progenitor cell differentiation Source: BHF-UCL
  54. male genitalia development Source: UniProtKB
  55. mesenchymal cell proliferation involved in lung development Source: Ensembl
  56. mesenchymal smoothened signaling pathway involved in prostate gland development Source: Ensembl
  57. metanephric mesenchymal cell proliferation involved in metanephros development Source: UniProtKB
  58. metanephros development Source: UniProtKB
  59. midbrain development Source: UniProtKB
  60. multicellular structure septum development Source: Ensembl
  61. myoblast differentiation Source: Ensembl
  62. myotube differentiation Source: Ensembl
  63. negative regulation of alpha-beta T cell differentiation Source: Ensembl
  64. negative regulation of apoptotic process Source: UniProt
  65. negative regulation of canonical Wnt signaling pathway Source: Ensembl
  66. negative regulation of cell differentiation Source: UniProtKB
  67. negative regulation of cell migration Source: UniProtKB
  68. negative regulation of cholesterol efflux Source: BHF-UCL
  69. negative regulation of kidney smooth muscle cell differentiation Source: UniProtKB
  70. negative regulation of mesenchymal cell apoptotic process Source: Ensembl
  71. negative regulation of proteasomal ubiquitin-dependent protein catabolic process Source: Ensembl
  72. negative regulation of T cell proliferation Source: Ensembl
  73. negative regulation of transcription elongation from RNA polymerase II promoter Source: Ensembl
  74. negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  75. negative regulation of ureter smooth muscle cell differentiation Source: UniProtKB
  76. negative thymic T cell selection Source: UniProtKB
  77. neural crest cell migration Source: UniProtKB
  78. neuroblast proliferation Source: UniProtKB
  79. neuron fate commitment Source: UniProtKB
  80. odontogenesis of dentin-containing tooth Source: Ensembl
  81. oligodendrocyte development Source: Ensembl
  82. organ formation Source: Ensembl
  83. osteoblast development Source: Ensembl
  84. palate development Source: Ensembl
  85. pancreas development Source: Ensembl
  86. patterning of blood vessels Source: UniProtKB
  87. pattern specification process Source: UniProtKB
  88. polarity specification of anterior/posterior axis Source: UniProt
  89. positive regulation of alpha-beta T cell differentiation Source: UniProtKB
  90. positive regulation of cell division Source: BHF-UCL
  91. positive regulation of cell proliferation Source: UniProtKB
  92. positive regulation of epithelial cell proliferation involved in prostate gland development Source: Ensembl
  93. positive regulation of hh target transcription factor activity Source: BHF-UCL
  94. positive regulation of immature T cell proliferation in thymus Source: BHF-UCL
  95. positive regulation of kidney smooth muscle cell differentiation Source: UniProtKB
  96. positive regulation of mesenchymal cell proliferation involved in ureter development Source: UniProtKB
  97. positive regulation of neuroblast proliferation Source: Ensembl
  98. positive regulation of oligodendrocyte differentiation Source: Ensembl
  99. positive regulation of protein import into nucleus Source: Ensembl
  100. positive regulation of sclerotome development Source: BHF-UCL
  101. positive regulation of skeletal muscle cell proliferation Source: Ensembl
  102. positive regulation of skeletal muscle tissue development Source: Ensembl
  103. positive regulation of smoothened signaling pathway Source: UniProtKB
  104. positive regulation of striated muscle cell differentiation Source: Ensembl
  105. positive regulation of T cell differentiation in thymus Source: UniProtKB
  106. positive regulation of transcription, DNA-templated Source: BHF-UCL
  107. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  108. positive regulation of ureter smooth muscle cell differentiation Source: UniProtKB
  109. positive regulation of Wnt signaling pathway Source: Ensembl
  110. positive thymic T cell selection Source: UniProtKB
  111. primary prostatic bud elongation Source: Ensembl
  112. prostate epithelial cord elongation Source: Ensembl
  113. prostate gland development Source: UniProtKB
  114. protein localization to nucleus Source: Ensembl
  115. regulation of cell proliferation Source: UniProtKB
  116. regulation of mesenchymal cell proliferation involved in prostate gland development Source: Ensembl
  117. regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry Source: BHF-UCL
  118. regulation of odontogenesis Source: BHF-UCL
  119. regulation of prostatic bud formation Source: Ensembl
  120. regulation of protein localization to nucleus Source: BHF-UCL
  121. regulation of proteolysis Source: UniProtKB
  122. renal system development Source: UniProtKB
  123. right lung development Source: Ensembl
  124. salivary gland cavitation Source: Ensembl
  125. smoothened signaling pathway Source: UniProtKB
  126. smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation Source: Ensembl
  127. somite development Source: BHF-UCL
  128. spinal cord dorsal/ventral patterning Source: Ensembl
  129. spinal cord motor neuron differentiation Source: Ensembl
  130. stem cell development Source: UniProtKB
  131. striated muscle tissue development Source: Ensembl
  132. T cell differentiation in thymus Source: BHF-UCL
  133. telencephalon regionalization Source: Ensembl
  134. thalamus development Source: Ensembl
  135. thymus development Source: UniProtKB
  136. thyroid gland development Source: Ensembl
  137. trachea morphogenesis Source: Ensembl
  138. vasculogenesis Source: UniProtKB
  139. ventral midline development Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Hydrolase, Protease

Keywords - Ligandi

Calcium, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiREACT_18372. Class B/2 (Secretin family receptors).
SignaLinkiQ15465.

Protein family/group databases

MEROPSiC46.002.

Names & Taxonomyi

Protein namesi
Recommended name:
Sonic hedgehog protein
Short name:
SHH
Alternative name(s):
HHG-1
Cleaved into the following 2 chains:
Gene namesi
Name:SHH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 7

Organism-specific databases

HGNCiHGNC:10848. SHH.

Subcellular locationi

Chain Sonic hedgehog protein C-product : Secretedextracellular space By similarity
Note: The C-terminal peptide diffuses from the cell By similarity.1 Publication
Chain Sonic hedgehog protein N-product : Cell membrane; Lipid-anchor By similarity. Cell membrane
Note: The N-product either remains associated with lipid rafts at the cell surface, or forms freely diffusible active multimers with its hydrophobic lipid-modified N- and C-termini buried inside By similarity.1 Publication

GO - Cellular componenti

  1. cell surface Source: UniProtKB
  2. extracellular matrix Source: Ensembl
  3. extracellular space Source: UniProtKB
  4. membrane raft Source: UniProtKB
  5. nucleus Source: Ensembl
  6. plasma membrane Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A 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).
Note: The disease is caused by mutations affecting the gene represented in this entry.1 Publication
Holoprosencephaly 3 (HPE3) [MIM:142945]: A 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.
Note: The disease is caused by mutations affecting the gene represented in this entry.12 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti6 – 61R → T in HPE3. 2 Publications
VAR_023804
Natural varianti17 – 171L → P in HPE3. 1 Publication
VAR_062592
Natural varianti26 – 261P → L in HPE3. 1 Publication
VAR_062593
Natural varianti27 – 271G → A in HPE3. 2 Publications
VAR_039888
Natural varianti31 – 311G → 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 Publications
Corresponds to variant rs28936675 [ dbSNP | Ensembl ].
VAR_003619
Natural varianti39 – 391L → P in HPE3. 1 Publication
VAR_062594
Natural varianti53 – 531E → K in HPE3. 1 Publication
VAR_062595
Natural varianti83 – 831D → V in HPE3. 1 Publication
VAR_062596
Natural varianti84 – 841I → F in HPE3. 1 Publication
VAR_062597
Natural varianti88 – 881D → 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 Publications
VAR_009163
Natural varianti100 – 1001Q → 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
VAR_009164
Natural varianti102 – 1021C → R in HPE3. 1 Publication
VAR_062598
Natural varianti102 – 1021C → Y in HPE3. 1 Publication
VAR_062599
Natural varianti106 – 1072Missing in HPE3.
VAR_023805
Natural varianti109 – 1091L → F in HPE3. 1 Publication
VAR_062600
Natural varianti110 – 1101A → D in HPE3. 2 Publications
VAR_023806
Natural varianti110 – 1101A → T in HPE3. 1 Publication
VAR_062601
Natural varianti111 – 1111I → N in HPE3. 2 Publications
VAR_039889
Natural varianti115 – 1151N → K in HPE3; familial; in the mouse sequence shows no change in activities at different temperatures. 3 Publications
VAR_009165
Natural varianti117 – 1171W → 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 Publications
VAR_003620
Natural varianti117 – 1171W → 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 Publications
VAR_003621
Natural varianti124 – 1241V → M in HPE3. 1 Publication
VAR_062602
Natural varianti136 – 1361E → K in HPE3. 1 Publication
VAR_062603
Natural varianti140 – 1401H → P in HPE3. 2 Publications
VAR_039890
Natural varianti140 – 1401H → Q in HPE3. 3 Publications
VAR_039891
Natural varianti143 – 1431G → D in HPE3. 1 Publication
VAR_062604
Natural varianti144 – 1441R → P in HPE3. 1 Publication
VAR_062605
Natural varianti147 – 1471D → N in HPE3. 1 Publication
VAR_062606
Natural varianti150 – 1501T → K in HPE3. 1 Publication
VAR_062607
Natural varianti150 – 1501T → R in HPE3. 2 Publications
VAR_023807
Natural varianti156 – 1561S → R in HPE3. 1 Publication
VAR_062608
Natural varianti170 – 1701F → C in HPE3. 1 Publication
VAR_062609
Natural varianti171 – 1711D → H in HPE3. 1 Publication
VAR_062610
Natural varianti176 – 1783Missing in HPE3.
VAR_023808
Natural varianti183 – 1831C → F in HPE3. 2 Publications
VAR_039892
Natural varianti183 – 1831C → R in HPE3. 1 Publication
VAR_062611
Natural varianti183 – 1831C → Y in HPE3. 1 Publication
VAR_062612
Natural varianti184 – 1841S → L in HPE3. 1 Publication
VAR_062613
Natural varianti188 – 1881E → Q in HPE3; familial. 4 Publications
VAR_009166
Natural varianti196 – 2005Missing in HPE3.
VAR_062614
Natural varianti196 – 1961G → E in HPE3. 1 Publication
VAR_062615
Natural varianti197 – 1971G → V in HPE3. 1 Publication
VAR_062616
Natural varianti198 – 1981C → F in HPE3. 1 Publication
VAR_062617
Natural varianti198 – 1981C → S in HPE3. 1 Publication
VAR_062618
Natural varianti218 – 2181L → P in HPE3. 2 Publications
VAR_062619
Natural varianti222 – 2221D → N in HPE3; familial. 3 Publications
VAR_009167
Natural varianti224 – 2241V → E in HPE3. 2 Publications
VAR_009168
Natural varianti226 – 2261A → T in HPE3; familial. 2 Publications
VAR_009169
Natural varianti231 – 2311G → V in HPE3. 1 Publication
VAR_062620
Natural varianti232 – 2321R → G in HPE3. 1 Publication
VAR_062621
Natural varianti234 – 2341L → P in HPE3. 1 Publication
VAR_062622
Natural varianti236 – 2361S → N in HPE3. 1 Publication
VAR_062623
Natural varianti236 – 2361S → R in HPE3; familial. 2 Publications
VAR_009170
Natural varianti241 – 2411F → L in HPE3. 1 Publication
VAR_062624
Natural varianti241 – 2411F → V in HPE3. 1 Publication
VAR_062625
Natural varianti255 – 2551I → N in HPE3. 1 Publication
VAR_062626
Natural varianti263 – 2697Missing in HPE3; sporadic.
VAR_009171
Natural varianti267 – 2671T → I in HPE3. 2 Publications
VAR_039893
Natural varianti271 – 2711L → P in HPE3. 2 Publications
VAR_023809
Natural varianti275 – 2751A → E in HPE3. 1 Publication
VAR_062627
Natural varianti280 – 2801S → W in HPE3. 1 Publication
VAR_062628
Natural varianti290 – 2901G → D in HPE3; sporadic. 2 Publications
Corresponds to variant rs104894047 [ dbSNP | Ensembl ].
VAR_009172
Natural varianti296 – 2961G → A in HPE3; unknown pathological significance. 1 Publication
VAR_062629
Natural varianti310 – 3101R → C in HPE3. 1 Publication
VAR_062630
Natural varianti321 – 3211R → S in HPE3. 1 Publication
VAR_062631
Natural varianti332 – 3321V → A in HPE3 and SMMCI. 3 Publications
VAR_023810
Natural varianti346 – 3461A → V in HPE3. 1 Publication
VAR_062632
Natural varianti347 – 3471P → L in HPE3. 1 Publication
VAR_062633
Natural varianti347 – 3471P → Q in HPE3. 2 Publications
VAR_023811
Natural varianti347 – 3471P → R in HPE3. 1 Publication
VAR_062634
Natural varianti354 – 3541I → T in HPE3. 2 Publications
VAR_023812
Natural varianti362 – 3621S → L in HPE3. 1 Publication
VAR_062635
Natural varianti363 – 3631C → Y in HPE3. 2 Publications
VAR_062636
Natural varianti364 – 3641Y → C in HPE3. 1 Publication
VAR_062637
Natural varianti373 – 3731A → T in HPE3. 2 Publications
VAR_039894
Natural varianti374 – 3741H → R in HPE3. 1 Publication
VAR_062638
Natural varianti376 – 3761A → D in HPE3. 1 Publication
VAR_062639
Natural varianti377 – 3771F → S in HPE3. 1 Publication
VAR_062640
Natural varianti378 – 3803Missing in HPE3; familial.
VAR_009173
Natural varianti381 – 3811R → P in HPE3. 2 Publications
VAR_023813
Natural varianti382 – 3821L → P in HPE3. 1 Publication
VAR_062641
Natural varianti383 – 3831A → T in HPE3; sporadic. 2 Publications
VAR_009174
Natural varianti391 – 3911A → T in HPE3; unknown pathological significance. 1 Publication
VAR_062642
Natural varianti402 – 4098Missing in HPE3; unknown pathological significance.
VAR_062643
Natural varianti404 – 4085Missing in HPE3; familial.
VAR_009175
Natural varianti405 – 4095Missing in HPE3; unknown pathological significance.
VAR_062644
Natural varianti411 – 4111G → GG in HPE3; unknown pathological significance. 1 Publication
VAR_062645
Natural varianti416 – 4161T → A in HPE3; unknown pathological significance. 1 Publication
VAR_062646
Natural varianti424 – 4241P → A in HPE3; familial. 2 Publications
VAR_009176
Natural varianti435 – 4351Y → N in HPE3. 1 Publication
VAR_062647
Natural varianti436 – 4361S → L in HPE3; sporadic. 2 Publications
VAR_009177
Natural varianti456 – 4561G → R in HPE3; unknown pathological significance. 1 Publication
VAR_062648
Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor.
Note: The disease is caused by mutations affecting the gene represented in this entry.2 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti111 – 1111I → F in SMMCI. 2 Publications
VAR_017883
Natural varianti332 – 3321V → A in HPE3 and SMMCI. 3 Publications
VAR_023810
Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development.
Note: 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.2 Publications
Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal.
Note: 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 (1 Publication).

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi24 – 241C → S: Abolishes palmitoylation. 1 Publication

Keywords - Diseasei

Disease mutation, Holoprosencephaly, Microphthalmia

Organism-specific databases

MIMi142945. phenotype.
147250. phenotype.
174500. phenotype.
611638. phenotype.
Orphaneti93925. Alobar holoprosencephaly.
98938. Colobomatous microphthalmia.
3332. Hypoplastic tibiae - postaxial polydactyly.
93924. Lobar holoprosencephaly.
280200. Microform holoprosencephaly.
93926. Midline interhemispheric variant of holoprosencephaly.
194. Ocular coloboma.
295150. Polydactyly of a triphalangeal thumb, bilateral.
295148. Polydactyly of a triphalangeal thumb, unilateral.
295071. Radial hemimelia, bilateral.
295069. Radial hemimelia, unilateral.
799. Schizencephaly.
220386. Semilobar holoprosencephaly.
280195. Septopreoptic holoprosencephaly.
2286. Solitary median maxillary central incisor syndrome.
93405. Syndactyly type 4.
2950. Triphalangeal thumb - polysyndactyly syndrome.
PharmGKBiPA35752.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 23231 PublicationAdd
BLAST
Chaini24 – 462439Sonic hedgehog proteinPRO_0000013208Add
BLAST
Chaini24 – 197174Sonic hedgehog protein N-productPRO_0000013209Add
BLAST
Chaini198 – 462265Sonic hedgehog protein C-productPRO_0000013210Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Lipidationi24 – 241N-palmitoyl cysteine1 Publication
Lipidationi197 – 1971Cholesterol glycine ester By similarity
Glycosylationi278 – 2781N-linked (GlcNAc...)1 Publication

Post-translational modificationi

The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. 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 (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity.
Cholesterylation is required for N-product targeting to lipid rafts and multimerization By similarity.
N-palmitoylation of Cys-24 by HHAT is required for N-product multimerization and full activity By similarity.1 Publication

Keywords - PTMi

Autocatalytic cleavage, Glycoprotein, Lipoprotein, Palmitate

Proteomic databases

PaxDbiQ15465.
PRIDEiQ15465.

PTM databases

PhosphoSiteiQ15465.

Expressioni

Tissue specificityi

Expressed in fetal intestine, liver, lung, and kidney. Not expressed in adult tissues.

Gene expression databases

ArrayExpressiQ15465.
BgeeiQ15465.
CleanExiHS_SHH.
GenevestigatoriQ15465.

Organism-specific databases

HPAiCAB018966.

Interactioni

Subunit structurei

Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus. N-product is active as a multimer. Interacts with BOC and CDON By similarity. Interacts with HHIP.1 Publication

Protein-protein interaction databases

BioGridi112365. 6 interactions.
STRINGi9606.ENSP00000297261.

Structurei

Secondary structure

1
462
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi30 – 323
Beta strandi47 – 515
Turni56 – 594
Helixi72 – 754
Beta strandi84 – 863
Beta strandi91 – 933
Helixi94 – 963
Helixi100 – 11617
Beta strandi122 – 1287
Helixi139 – 1424
Beta strandi145 – 1506
Helixi155 – 1573
Helixi158 – 16710
Beta strandi171 – 1777
Beta strandi180 – 1845
Helixi188 – 1903

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3HO5X-ray3.01H29-197[»]
3M1NX-ray1.85A/B23-197[»]
3MXWX-ray1.83A29-197[»]
ProteinModelPortaliQ15465.
SMRiQ15465. Positions 25-190, 198-365.

Miscellaneous databases

EvolutionaryTraceiQ15465.

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi407 – 4115Poly-Gly

Domaini

The 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

Sequence similaritiesi

Belongs to the hedgehog family.

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiNOG250647.
HOGENOMiHOG000233428.
HOVERGENiHBG005480.
InParanoidiQ15465.
KOiK11988.
OMAiHSWAHRA.
OrthoDBiEOG779NZ5.
PhylomeDBiQ15465.
TreeFamiTF106458.

Family and domain databases

Gene3Di2.170.16.10. 1 hit.
3.30.1380.10. 1 hit.
InterProiIPR001657. Hedgehog.
IPR028992. Hedgehog/Intein_dom.
IPR009045. Hedgehog_sig/DD-Pept_Zn-bd_dom.
IPR000320. Hedgehog_signalling_dom.
IPR001767. Hint_dom.
IPR003586. Hint_dom_C.
IPR003587. Hint_dom_N.
IPR006141. Intein_splice_site.
[Graphical view]
PfamiPF01085. HH_signal. 1 hit.
PF01079. Hint. 1 hit.
[Graphical view]
PIRSFiPIRSF009400. Peptidase_C46. 1 hit.
PRINTSiPR00632. SONICHHOG.
SMARTiSM00305. HintC. 1 hit.
SM00306. HintN. 1 hit.
[Graphical view]
SUPFAMiSSF51294. SSF51294. 1 hit.
SSF55166. SSF55166. 1 hit.
PROSITEiPS50817. INTEIN_N_TER. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q15465-1 [UniParc]FASTAAdd to Basket

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MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN    50
VAEKTLGASG RYEGKISRNS ERFKELTPNY NPDIIFKDEE NTGADRLMTQ 100
RCKDKLNALA ISVMNQWPGV KLRVTEGWDE DGHHSEESLH YEGRAVDITT 150
SDRDRSKYGM LARLAVEAGF DWVYYESKAH IHCSVKAENS VAAKSGGCFP 200
GSATVHLEQG GTKLVKDLSP GDRVLAADDQ GRLLYSDFLT FLDRDDGAKK 250
VFYVIETREP RERLLLTAAH LLFVAPHNDS ATGEPEASSG SGPPSGGALG 300
PRALFASRVR PGQRVYVVAE RDGDRRLLPA AVHSVTLSEE AAGAYAPLTA 350
QGTILINRVL ASCYAVIEEH SWAHRAFAPF RLAHALLAAL APARTDRGGD 400
SGGGDRGGGG GRVALTAPGA ADAPGAGATA GIHWYSQLLY QIGTWLLDSE 450
ALHPLGMAVK SS 462
Length:462
Mass (Da):49,607
Last modified:November 1, 1996 - v1
Checksum:iDD687AFA582A4749
GO

Mass spectrometryi

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

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti6 – 61R → T in HPE3. 2 Publications
VAR_023804
Natural varianti17 – 171L → P in HPE3. 1 Publication
VAR_062592
Natural varianti26 – 261P → L in HPE3. 1 Publication
VAR_062593
Natural varianti27 – 271G → A in HPE3. 2 Publications
VAR_039888
Natural varianti31 – 311G → 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 Publications
Corresponds to variant rs28936675 [ dbSNP | Ensembl ].
VAR_003619
Natural varianti39 – 391L → P in HPE3. 1 Publication
VAR_062594
Natural varianti53 – 531E → K in HPE3. 1 Publication
VAR_062595
Natural varianti83 – 831D → V in HPE3. 1 Publication
VAR_062596
Natural varianti84 – 841I → F in HPE3. 1 Publication
VAR_062597
Natural varianti88 – 881D → 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 Publications
VAR_009163
Natural varianti100 – 1001Q → 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
VAR_009164
Natural varianti102 – 1021C → R in HPE3. 1 Publication
VAR_062598
Natural varianti102 – 1021C → Y in HPE3. 1 Publication
VAR_062599
Natural varianti106 – 1072Missing in HPE3.
VAR_023805
Natural varianti109 – 1091L → F in HPE3. 1 Publication
VAR_062600
Natural varianti110 – 1101A → D in HPE3. 2 Publications
VAR_023806
Natural varianti110 – 1101A → T in HPE3. 1 Publication
VAR_062601
Natural varianti111 – 1111I → F in SMMCI. 2 Publications
VAR_017883
Natural varianti111 – 1111I → N in HPE3. 2 Publications
VAR_039889
Natural varianti115 – 1151N → K in HPE3; familial; in the mouse sequence shows no change in activities at different temperatures. 3 Publications
VAR_009165
Natural varianti117 – 1171W → 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 Publications
VAR_003620
Natural varianti117 – 1171W → 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 Publications
VAR_003621
Natural varianti124 – 1241V → M in HPE3. 1 Publication
VAR_062602
Natural varianti136 – 1361E → K in HPE3. 1 Publication
VAR_062603
Natural varianti140 – 1401H → P in HPE3. 2 Publications
VAR_039890
Natural varianti140 – 1401H → Q in HPE3. 3 Publications
VAR_039891
Natural varianti143 – 1431G → D in HPE3. 1 Publication
VAR_062604
Natural varianti144 – 1441R → P in HPE3. 1 Publication
VAR_062605
Natural varianti147 – 1471D → N in HPE3. 1 Publication
VAR_062606
Natural varianti150 – 1501T → K in HPE3. 1 Publication
VAR_062607
Natural varianti150 – 1501T → R in HPE3. 2 Publications
VAR_023807
Natural varianti156 – 1561S → R in HPE3. 1 Publication
VAR_062608
Natural varianti170 – 1701F → C in HPE3. 1 Publication
VAR_062609
Natural varianti171 – 1711D → H in HPE3. 1 Publication
VAR_062610
Natural varianti176 – 1783Missing in HPE3.
VAR_023808
Natural varianti183 – 1831C → F in HPE3. 2 Publications
VAR_039892
Natural varianti183 – 1831C → R in HPE3. 1 Publication
VAR_062611
Natural varianti183 – 1831C → Y in HPE3. 1 Publication
VAR_062612
Natural varianti184 – 1841S → L in HPE3. 1 Publication
VAR_062613
Natural varianti188 – 1881E → Q in HPE3; familial. 4 Publications
VAR_009166
Natural varianti196 – 2005Missing in HPE3.
VAR_062614
Natural varianti196 – 1961G → E in HPE3. 1 Publication
VAR_062615
Natural varianti197 – 1971G → V in HPE3. 1 Publication
VAR_062616
Natural varianti198 – 1981C → F in HPE3. 1 Publication
VAR_062617
Natural varianti198 – 1981C → S in HPE3. 1 Publication
VAR_062618
Natural varianti218 – 2181L → P in HPE3. 2 Publications
VAR_062619
Natural varianti222 – 2221D → N in HPE3; familial. 3 Publications
VAR_009167
Natural varianti224 – 2241V → E in HPE3. 2 Publications
VAR_009168
Natural varianti226 – 2261A → T in HPE3; familial. 2 Publications
VAR_009169
Natural varianti231 – 2311G → V in HPE3. 1 Publication
VAR_062620
Natural varianti232 – 2321R → G in HPE3. 1 Publication
VAR_062621
Natural varianti234 – 2341L → P in HPE3. 1 Publication
VAR_062622
Natural varianti236 – 2361S → N in HPE3. 1 Publication
VAR_062623
Natural varianti236 – 2361S → R in HPE3; familial. 2 Publications
VAR_009170
Natural varianti241 – 2411F → L in HPE3. 1 Publication
VAR_062624
Natural varianti