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Protein

Sonic hedgehog protein

Gene

shh

Organism
Xenopus laevis (African clawed frog)
Status
Reviewed-Annotation score: -Experimental evidence at transcript leveli

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 (By similarity). 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 (By similarity). In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (By similarity).By similarity3 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. Once released, the fully processed Shh can signal within embryonic tissues both at short and long-range.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi90Calcium 1By similarity1
Metal bindingi91Calcium 1By similarity1
Metal bindingi91Calcium 2By similarity1
Metal bindingi96Calcium 1By similarity1
Metal bindingi126Calcium 1; via carbonyl oxygenBy similarity1
Metal bindingi127Calcium 1By similarity1
Metal bindingi127Calcium 2By similarity1
Metal bindingi130Calcium 2By similarity1
Metal bindingi132Calcium 2By similarity1
Metal bindingi141ZincBy similarity1
Metal bindingi148ZincBy similarity1
Metal bindingi183ZincBy similarity1
Sitei266Involved in auto-cleavageBy similarity1
Sitei269Essential for auto-cleavageBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

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

Protein family/group databases

MEROPSiC46.002

Names & Taxonomyi

Protein namesi
Recommended name:
Sonic hedgehog protein
Alternative name(s):
Shh unprocessed N-terminal signaling and C-terminal autoprocessing domainsBy similarity
Short name:
ShhNCBy similarity
VHH-1
X-SHH
Cleaved into the following chain:
Alternative name(s):
Shh N-terminal processed signaling domainsBy similarity
Short name:
ShhNpBy similarity
Gene namesi
Name:shh
OrganismiXenopus laevis (African clawed frog)
Taxonomic identifieri8355 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiAmphibiaBatrachiaAnuraPipoideaPipidaeXenopodinaeXenopusXenopus

Organism-specific databases

XenbaseiXB-GENE-864913 shh

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, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24By similarityAdd BLAST24
ChainiPRO_000001322025 – 444Sonic hedgehog proteinAdd BLAST420
ChainiPRO_000001322125 – 198Sonic hedgehog protein N-productAdd BLAST174

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi25N-palmitoyl cysteineBy similarity1
Lipidationi198Cholesterol glycine esterBy similarity1

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 (By similarity). 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).By similarity
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 (By similarity).By similarity
Sonic hedgehog protein N-product: The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding) (By similarity). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (By similarity). The cleavage reduced the interactions with heparan sulfate (By similarity). The cleavage is enhanced by SCUBE2 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei198 – 199Cleavage; by autolysisBy similarity2

Keywords - PTMi

Autocatalytic cleavage, Lipoprotein, Palmitate

Proteomic databases

PRIDEiQ92000

Expressioni

Tissue specificityi

Strongly expressed in notochord and neural floor plate during embryogenesis. In tadpole, high expression is observed in pancreas/stomach, moderate expression in tail, and low expression in intestine, brain, and hind limb.3 Publications

Developmental stagei

First detected at the neurula (stages 16-17). First peak of expression around tadpole hatching (stages 33-40). High expression observed in intestine at the climax of morphogenesis (stages 60-62) when intestine epithelial undergoes morphogenesis.3 Publications

Inductioni

By thyroid hormone.1 Publication

Interactioni

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 (By similarity). Interacts with BOC and CDON (By similarity). Interacts with HHIP (By similarity). Interacts with DISP1 via its cholesterol anchor (By similarity). Interacts with SCUBE2 (By similarity).By similarity

Structurei

3D structure databases

ProteinModelPortaliQ92000
SMRiQ92000
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati386 – 39318
Repeati394 – 40128
Repeati403 – 40937

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni386 – 4093 X 8 AA tandem repeats of Q-V-D-L-Q-S-H-HAdd BLAST24

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi33 – 39Cardin-WeintraubBy similarity7

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.By similarity
Sonic hedgehog protein N-product: The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized ShhNp (By similarity). The N-terminal palmitoylated peptide is cleaved at the Heparan sulfate-binding Cardin-Weintraub (CW) motif site (By similarity). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (By similarity).By similarity

Sequence similaritiesi

Belongs to the hedgehog family.Curated

Keywords - Domaini

Repeat, Signal

Phylogenomic databases

HOVERGENiHBG005480
KOiK11988

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

Sequencei

Sequence statusi: Complete.

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

Q92000-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLVATQSLLL LSFICTLVTP PGLACGPGRG IGKRRHPKKL TPLAYKQFIP
60 70 80 90 100
NVAEKTLGAS GRYEGKITRN SDCFKELTPN YNPDIMFKDE ESTGADRLMT
110 120 130 140 150
QRCKDKLNAL AISVMNQWPG VKLRVTEGWD EDGHHLEESL HYEGRAVDIT
160 170 180 190 200
TSDRDRSKYG MLGRLAVEAG FDWVYYESKA HIHCSVKAEN SVAAKSGGCF
210 220 230 240 250
PAGARVMVEF GGTKAVKDLR PGDRVLSSDP QGNLLYSDFL MFIDQERDVK
260 270 280 290 300
KLFYVIETSQ RKIRLTAAHL LFVAQTKVNG TRSFKSVFAS NIQPGDLIYT
310 320 330 340 350
ADPKTMTLKA VKVEKVDLEE DTGAYAPLTA HGTVVIDQVL ASCYAVIEEH
360 370 380 390 400
TWAHLAFAPL RFGMSLSSYI YPRDSSPPSG LQPHHQVDLQ SHHQVDLQSH
410 420 430 440
HQVDLQSHHQ LEGIHWYSQL LYQIGTWLLD SNSLHPLGMA TKSS
Length:444
Mass (Da):49,453
Last modified:November 1, 1996 - v1
Checksum:i73B4E4932FA2EFF2
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti5 – 9TQSLL → NSNLCW in AAA49981 (PubMed:7551564).Curated5
Sequence conflicti302 – 319DPKTM…KVDLE → ESQDHDLEGRGKWRRLILR in AAA49981 (PubMed:7551564).CuratedAdd BLAST18
Sequence conflicti432N → S in AAA49981 (PubMed:7551564).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L39213 mRNA Translation: AAC42227.1
U26314 mRNA Translation: AAA85162.1
L35248 mRNA Translation: AAA49981.1
PIRiS56765
RefSeqiNP_001081782.1, NM_001088313.1
UniGeneiXl.866

Genome annotation databases

GeneIDi398047
KEGGixla:398047

Similar proteinsi

Entry informationi

Entry nameiSHH_XENLA
AccessioniPrimary (citable) accession number: Q92000
Secondary accession number(s): Q91894
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 1, 1996
Last modified: May 23, 2018
This is version 122 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Documents

  1. SIMILARITY comments
    Index of protein domains and families

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