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Q15465

- SHH_HUMAN

UniProt

Q15465 - SHH_HUMAN

Protein

Sonic hedgehog protein

Gene

SHH

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 173 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    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.By similarity

    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 – 1401Zinc2 Publications
    Metal bindingi147 – 1471Zinc2 Publications
    Metal bindingi182 – 1821Zinc2 Publications
    Sitei197 – 1982Cleavage; by autolysisBy similarity
    Sitei243 – 2431Involved in cholesterol transferBy similarity
    Sitei267 – 2671Involved in auto-cleavageBy similarity
    Sitei270 – 2701Essential for auto-cleavageBy 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

    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
    Chain Sonic hedgehog protein N-product : Cell membrane By similarity; 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

    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

    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).1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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.11 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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. 3 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. 2 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. 3 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. 2 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. 3 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. 3 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. 3 Publications
    VAR_009166
    Natural varianti196 – 2005Missing in HPE3. 1 Publication
    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.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    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.2 Publications
    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.
    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 (PubMed:12837695).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 esterBy 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

    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.By similarity3 Publications

    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.
    ModBaseiSearch...
    MobiDBiSearch...

    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.Curated

    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

    « Hide

    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. 3 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. 2 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. 3 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. 2 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. 3 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. 3 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. 3 Publications
    VAR_009166
    Natural varianti196 – 2005Missing in HPE3. 1 Publication
    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