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Protein

Protein hedgehog

Gene

hh

Organism
Drosophila melanogaster (Fruit fly)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Intercellular signal essential for a variety of patterning events during development. Establishes the anterior-posterior axis of the embryonic segments and patterns the larval imaginal disks. Binds to the patched (ptc) receptor, which functions in association with smoothened (smo), to activate the transcription of target genes wingless (wg), decapentaplegic (dpp) and ptc. In the absence of hh, ptc represses the constitutive signaling activity of smo through fused (fu). Essential component of a signaling pathway which regulates the Duox-dependent gut immune response to bacterial uracil; required to activate Cad99C-dependent endosome formation, norpA-dependent Ca2+ mobilization and p38 MAPK, which are essential steps in the Duox-dependent production of reactive oxygen species (ROS) in response to intestinal bacterial infection (PubMed:25639794). During photoreceptor differentiation, it up-regulates transcription of Ubr3, which in turn promotes the hh-signaling pathway by mediating the ubiquitination and degradation of cos (PubMed:27195754).2 Publications
The hedgehog protein N-product constitutes the active species in both local and long-range signaling, whereas the C-terminal product has no signaling activity. It acts as a morphogen, and diffuses long distances despite its lipidation. Heparan sulfate proteoglycans of the extracellular matrix play an essential role in diffusion. Lipophorin is required for diffusion, probably by acting as vehicle for its movement, explaining how it can spread over long distances despite its lipidation.
The hedgehog protein C-product, which mediates the autocatalytic activity, has no signaling activity.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi149Calcium 1By similarity1
Metal bindingi150Calcium 1By similarity1
Metal bindingi150Calcium 2By similarity1
Metal bindingi155Calcium 1By similarity1
Metal bindingi185Calcium 1; via carbonyl oxygenBy similarity1
Metal bindingi186Calcium 1By similarity1
Metal bindingi186Calcium 2By similarity1
Metal bindingi189Calcium 2By similarity1
Metal bindingi191Calcium 2By similarity1
Sitei303Involved in cholesterol transfer1
Sitei326Involved in auto-cleavage1
Sitei329Essential for auto-cleavage1 Publication1

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • morphogen activity Source: FlyBase
  • patched binding Source: FlyBase
  • peptidase activity Source: UniProtKB-KW
  • smoothened binding Source: UniProtKB

GO - Biological processi

  • analia development Source: FlyBase
  • anterior/posterior axis specification, embryo Source: FlyBase
  • anterior/posterior lineage restriction, imaginal disc Source: FlyBase
  • anterior commissure morphogenesis Source: FlyBase
  • anterior head segmentation Source: FlyBase
  • Bolwig's organ morphogenesis Source: FlyBase
  • cell-cell signaling involved in cell fate commitment Source: UniProtKB
  • compartment pattern specification Source: FlyBase
  • compound eye morphogenesis Source: FlyBase
  • compound eye photoreceptor cell differentiation Source: FlyBase
  • cytoneme assembly Source: FlyBase
  • developmental pigmentation Source: FlyBase
  • ectoderm development Source: FlyBase
  • embryonic pattern specification Source: UniProtKB
  • epidermis development Source: FlyBase
  • epithelial cell migration, open tracheal system Source: FlyBase
  • eye morphogenesis Source: FlyBase
  • foregut morphogenesis Source: FlyBase
  • genital disc anterior/posterior pattern formation Source: FlyBase
  • genital disc development Source: FlyBase
  • germ cell attraction Source: FlyBase
  • germ cell migration Source: FlyBase
  • germ-line stem cell division Source: FlyBase
  • glial cell migration Source: FlyBase
  • gonadal mesoderm development Source: FlyBase
  • heart development Source: FlyBase
  • heart formation Source: FlyBase
  • hindgut morphogenesis Source: FlyBase
  • imaginal disc-derived wing vein specification Source: FlyBase
  • imaginal disc growth Source: FlyBase
  • intein-mediated protein splicing Source: InterPro
  • labial disc development Source: FlyBase
  • leg disc morphogenesis Source: FlyBase
  • mesoderm development Source: FlyBase
  • morphogenesis of larval imaginal disc epithelium Source: FlyBase
  • mucosal immune response Source: FlyBase
  • negative regulation of protein ubiquitination Source: FlyBase
  • negative regulation of proteolysis Source: FlyBase
  • open tracheal system development Source: FlyBase
  • ovarian follicle cell development Source: FlyBase
  • ovarian follicle cell stalk formation Source: FlyBase
  • pole cell migration Source: FlyBase
  • positive regulation of fibroblast growth factor receptor signaling pathway Source: FlyBase
  • positive regulation of hh target transcription factor activity Source: FlyBase
  • positive regulation of protein localization to cell surface Source: FlyBase
  • posterior head segmentation Source: FlyBase
  • progression of morphogenetic furrow involved in compound eye morphogenesis Source: FlyBase
  • protein autoprocessing Source: UniProtKB
  • R8 cell fate specification Source: FlyBase
  • regulation of cell proliferation Source: FlyBase
  • regulation of epithelial cell migration, open tracheal system Source: FlyBase
  • regulation of mitotic cell cycle Source: FlyBase
  • regulation of transcription by RNA polymerase II Source: FlyBase
  • segment polarity determination Source: FlyBase
  • smoothened signaling pathway Source: FlyBase
  • somatic stem cell division Source: FlyBase
  • spiracle morphogenesis, open tracheal system Source: FlyBase
  • trunk segmentation Source: FlyBase
  • ventral midline development Source: FlyBase
  • wing disc anterior/posterior pattern formation Source: FlyBase
  • wing disc proximal/distal pattern formation Source: FlyBase

Keywordsi

Molecular functionDevelopmental protein, Hydrolase, Morphogen, Protease, Segmentation polarity protein
LigandCalcium, Metal-binding

Enzyme and pathway databases

ReactomeiR-DME-209338 Assembly of the 'signalling complexes'
R-DME-209471 Formation and transport of the N-HH ligand
R-DME-5358346 Hedgehog ligand biogenesis
R-DME-5362798 Release of Hh-Np from the secreting cell
R-DME-5632681 Ligand-receptor interactions
SignaLinkiQ02936

Protein family/group databases

MEROPSiC46.001

Names & Taxonomyi

Protein namesi
Recommended name:
Protein hedgehog
Cleaved into the following 2 chains:
Protein hedgehog N-product
Short name:
Hh-Np
Short name:
N-Hh
Alternative name(s):
C-Hh
Gene namesi
Name:hh
ORF Names:CG4637
OrganismiDrosophila melanogaster (Fruit fly)
Taxonomic identifieri7227 [NCBI]
Taxonomic lineageiEukaryotaMetazoaEcdysozoaArthropodaHexapodaInsectaPterygotaNeopteraHolometabolaDipteraBrachyceraMuscomorphaEphydroideaDrosophilidaeDrosophilaSophophora
Proteomesi
  • UP000000803 Componenti: Chromosome 3R

Organism-specific databases

FlyBaseiFBgn0004644 hh

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; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus, Secreted

Pathology & Biotechi

Disruption phenotypei

RNAi-mediated knockdown severely reduces adult survival following the ingestion of E.carotovora. Abolishes Cad99C-dependent formation of endosomes and DUOX-dependent up-regulation of reactive oxygen species (ROS) in the intestines of adults fed bacteria-derived uracil.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi85C → S: N-product is made but fails to undergo palmitoylation. 2 Publications1
Mutagenesisi303D → A: No cholesterol transfer. 1 Publication1
Mutagenesisi326T → A: Greatly reduced autoprocessing activity. 1 Publication1
Mutagenesisi329H → A: No autoprocessing activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
PropeptideiPRO_0000383048? – 84Sequence analysis
Signal peptidei1 – ?Sequence analysis
ChainiPRO_000001320285 – 471Protein hedgehogAdd BLAST387
ChainiPRO_000001320385 – 257Protein hedgehog N-productAdd BLAST173
ChainiPRO_0000013204258 – 471Protein hedgehog C-productAdd BLAST214

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi85N-palmitoyl cysteine1 Publication1
Lipidationi257Cholesterol glycine ester1 Publication1

Post-translational modificationi

The C-terminal domain displays autoproteolytic activity. Cleavage of the full-length hedgehog protein is followed by the covalent attachment of a cholesterol moiety to the C-terminus of the newly generated N-terminal fragment (N-product).
Cholesterol attachment plays an essential role in restricting the spatial distribution of hedgehog activity to the cell surface.
N-terminal palmitoylation of the hedgehog N-product is required for the embryonic and larval patterning activities of the hedgehog signal. Rasp acts within the secretory pathway to catalyze the N-terminal palmitoylation of Hh.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei257 – 258Cleavage; by autolysis1 Publication2

Keywords - PTMi

Autocatalytic cleavage, Lipoprotein, Palmitate

Proteomic databases

PaxDbiQ02936
PRIDEiQ02936

Miscellaneous databases

PMAP-CutDBiQ02936

Expressioni

Tissue specificityi

In embryos, expression starts at stage 5 as a few stripes at the anterior and posterior ends, this expands to 17 stripes during stages 8-11 (PubMed:8166882, PubMed:1280560, PubMed:1340474). Expression is also seen in CNS and some PNS cells until stage 13-14, and in foregut, hindgut and salivary glands (PubMed:1340474). In larvae, expression is seen in the posterior compartment of the wing, leg and antennal imaginal disks (PubMed:1394430, PubMed:1340474). In adults, high level of expression in specific regions of the proventriculus and hindgut, with slightly lower levels of expression in the posterior midgut (PubMed:25639794). Relatively low levels of expression in the anterior midgut region (PubMed:25639794).5 Publications

Developmental stagei

Expressed in embryos, larvae and pupae at high levels with maximum expression in 6-12 hours embryos and 0-24 hours pupae (PubMed:8166882, PubMed:1394430, PubMed:1280560, PubMed:1340474). Low levels of expression are seen in adults (PubMed:8166882, PubMed:1394430).4 Publications

Inductioni

Strongly up-regulated in the anterior midgut and the posterior midgut in response to bacterial uracil.1 Publication

Gene expression databases

BgeeiFBgn0004644
GenevisibleiQ02936 DM

Interactioni

Subunit structurei

Interacts with shf.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
ihogQ9VM646EBI-15609026,EBI-94134

GO - Molecular functioni

  • morphogen activity Source: FlyBase
  • patched binding Source: FlyBase
  • smoothened binding Source: UniProtKB

Protein-protein interaction databases

BioGridi67682, 75 interactors
DIPiDIP-51313N
IntActiQ02936, 2 interactors
STRINGi7227.FBpp0099945

Structurei

Secondary structure

1471
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi107 – 111Combined sources5
Turni116 – 119Combined sources4
Helixi131 – 135Combined sources5
Beta strandi144 – 146Combined sources3
Helixi160 – 176Combined sources17
Beta strandi182 – 188Combined sources7
Helixi199 – 202Combined sources4
Beta strandi205 – 210Combined sources6
Helixi215 – 217Combined sources3
Helixi218 – 228Combined sources11
Beta strandi231 – 234Combined sources4
Beta strandi241 – 244Combined sources4
Beta strandi264 – 267Combined sources4
Beta strandi272 – 274Combined sources3
Helixi275 – 277Combined sources3
Beta strandi283 – 287Combined sources5
Beta strandi293 – 317Combined sources25
Beta strandi322 – 325Combined sources4
Beta strandi330 – 335Combined sources6
Turni336 – 339Combined sources4
Beta strandi340 – 345Combined sources6
Helixi346 – 348Combined sources3
Beta strandi354 – 358Combined sources5
Turni360 – 362Combined sources3
Beta strandi365 – 393Combined sources29
Beta strandi396 – 400Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1AT0X-ray1.90A258-402[»]
2IBGX-ray2.20E/F/G/H99-248[»]
ProteinModelPortaliQ02936
SMRiQ02936
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ02936

Family & Domainsi

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi5 – 41Ser-richAdd BLAST37

Sequence similaritiesi

Belongs to the hedgehog family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG3638 Eukaryota
ENOG410XQA3 LUCA
GeneTreeiENSGT00390000001117
InParanoidiQ02936
KOiK06224
OMAiQHGQESL
OrthoDBiEOG091G0N90
PhylomeDBiQ02936

Family and domain databases

Gene3Di3.30.1380.10, 1 hit
InterProiView protein in InterPro
IPR001657 Hedgehog
IPR009045 Hedgehog_sig/DD-Pept_Zn-bd_sf
IPR000320 Hedgehog_signalling_dom
IPR001767 Hint_dom
IPR003586 Hint_dom_C
IPR003587 Hint_dom_N
IPR036844 Hint_dom_sf
IPR006141 Intein_N
PfamiView protein in Pfam
PF01085 HH_signal, 1 hit
PF01079 Hint, 1 hit
PIRSFiPIRSF009400 Peptidase_C46, 1 hit
PRINTSiPR00632 SONICHHOG
SMARTiView protein in SMART
SM00305 HintC, 1 hit
SM00306 HintN, 1 hit
SUPFAMiSSF51294 SSF51294, 1 hit
SSF55166 SSF55166, 1 hit
PROSITEiView protein in PROSITE
PS50817 INTEIN_N_TER, 1 hit

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Long (identifier: Q02936-1) [UniParc]FASTAAdd to basket
Also known as: A, B

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MDNHSSVPWA SAASVTCLSL DAKCHSSSSS SSSKSAASSI SAIPQEETQT
60 70 80 90 100
MRHIAHTQRC LSRLTSLVAL LLIVLPMVFS PAHSCGPGRG LGRHRARNLY
110 120 130 140 150
PLVLKQTIPN LSEYTNSASG PLEGVIRRDS PKFKDLVPNY NRDILFRDEE
160 170 180 190 200
GTGADRLMSK RCKEKLNVLA YSVMNEWPGI RLLVTESWDE DYHHGQESLH
210 220 230 240 250
YEGRAVTIAT SDRDQSKYGM LARLAVEAGF DWVSYVSRRH IYCSVKSDSS
260 270 280 290 300
ISSHVHGCFT PESTALLESG VRKPLGELSI GDRVLSMTAN GQAVYSEVIL
310 320 330 340 350
FMDRNLEQMQ NFVQLHTDGG AVLTVTPAHL VSVWQPESQK LTFVFADRIE
360 370 380 390 400
EKNQVLVRDV ETGELRPQRV VKVGSVRSKG VVAPLTREGT IVVNSVAASC
410 420 430 440 450
YAVINSQSLA HWGLAPMRLL STLEAWLPAK EQLHSSPKVV SSAQQQNGIH
460 470
WYANALYKVK DYVLPQSWRH D
Length:471
Mass (Da):52,150
Last modified:September 1, 2009 - v4
Checksum:i8ECD796A92FE7043
GO
Isoform Short (identifier: Q02936-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     161-192: RCKEKLNVLAYSVMNEWPGIRLLVTESWDEDY → VRKTLKHRKLVTKFVIHHWESFAYRNHCDKVT
     193-471: Missing.

Show »
Length:192
Mass (Da):21,323
Checksum:iC19D4D9EF4367D47
GO

Sequence cautioni

The sequence AAA28604 differs from that shown. Reason: Frameshift at positions 21 and 48.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti156R → G in AAA28604 (PubMed:8166882).Curated1
Sequence conflicti347D → H in AAA28604 (PubMed:8166882).Curated1
Sequence conflicti373V → L in AAA28604 (PubMed:8166882).Curated1
Sequence conflicti407Q → P in Z11840 (PubMed:1280560).Curated1

Mass spectrometryi

Molecular mass is 20238.44 Da from positions 85 - 257. Determined by MALDI. 1 Publication

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_002065161 – 192RCKEK…WDEDY → VRKTLKHRKLVTKFVIHHWE SFAYRNHCDKVT in isoform Short. CuratedAdd BLAST32
Alternative sequenceiVSP_002066193 – 471Missing in isoform Short. CuratedAdd BLAST279

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L05404 mRNA Translation: AAA28604.1 Frameshift.
L05405 Genomic DNA No translation available.
L02793 Unassigned DNA Translation: AAA16458.1
Z11840 Genomic DNA No translation available.
S66384 mRNA Translation: AAB28646.1
AE014297 Genomic DNA Translation: AAF56102.1
AE014297 Genomic DNA Translation: ABC66186.1
PIRiA46400
RefSeqiNP_001034065.1, NM_001038976.1 [Q02936-1]
UniGeneiDm.2371

Genome annotation databases

EnsemblMetazoaiFBtr0100506; FBpp0099945; FBgn0004644 [Q02936-1]
GeneIDi42737
KEGGidme:Dmel_CG4637
UCSCiCG4637-RA d. melanogaster [Q02936-1]
CG4637-RB d. melanogaster

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiHH_DROME
AccessioniPrimary (citable) accession number: Q02936
Secondary accession number(s): A4V396, Q9VCQ4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: September 1, 2009
Last modified: May 23, 2018
This is version 202 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programDrosophila annotation project

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Drosophila
    Drosophila: entries, gene names and cross-references to FlyBase
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

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