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Protein

Sonic hedgehog protein

Gene

Shh

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein 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 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
Sitei244Involved in cholesterol transferBy similarity1
Sitei268Involved in auto-cleavageBy similarity1
Sitei271Essential 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
Short name:
SHH
Alternative name(s):
Shh unprocessed N-terminal signaling and C-terminal autoprocessing domainsBy similarity
Short name:
ShhNCBy similarity
Cleaved into the following chain:
Alternative name(s):
Shh N-terminal processed signaling domainsBy similarity
Short name:
ShhNpBy similarity
Gene namesi
Name:ShhImported
Synonyms:Vhh-1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi3673. 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_000001321425 – 437Sonic hedgehog proteinAdd BLAST413
ChainiPRO_000001321525 – 198Sonic hedgehog protein N-productAdd BLAST174

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi25N-palmitoyl cysteineBy similarity1
Lipidationi198Cholesterol glycine esterBy similarity1
Glycosylationi279N-linked (GlcNAc...) asparagineSequence analysis1

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 autolysis2

Keywords - PTMi

Autocatalytic cleavage, Glycoprotein, Lipoprotein, Palmitate

Proteomic databases

PaxDbiQ63673.
PRIDEiQ63673.

Expressioni

Tissue specificityi

Expressed in the node, notochord, floor plate, and posterior limb bud mesenchyme.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 similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000008497.

Structurei

3D structure databases

ProteinModelPortaliQ63673.
SMRiQ63673.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

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

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi383 – 387Poly-Gly5

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

Signal

Phylogenomic databases

eggNOGiKOG3638. Eukaryota.
ENOG410XQA3. LUCA.
HOGENOMiHOG000233428.
HOVERGENiHBG005480.
InParanoidiQ63673.
KOiK11988.
PhylomeDBiQ63673.

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.

Q63673-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLLLLARCFL VALASSLLVC PGLACGPGRG FGKRQHPKKL TPLAYKQFIP
60 70 80 90 100
NVAEKTLGAS GRYEGKITRN SERFKELTPN YNPDIIFKDE ENTGADRLMT
110 120 130 140 150
QRCKDKLNAL AISVMNQWPG VKLRVTEGWD EDGHHSEESL HYEGRAVDIT
160 170 180 190 200
TSDRDRSKYG MLARLAVEAG FDWVYYESKA RIHCSVKAEN SVAAKSDGCF
210 220 230 240 250
PGSATVHLEQ GGTKLVKDLS PGDRVLAADD QGRLLYSDFL TFLDRDEGAK
260 270 280 290 300
KVFYVIETRE PRERLLLTAA HLLFVAPHND SGPTPGPSPL FASRVRPGQR
310 320 330 340 350
VYVVAERGGD RRLLPAAVHS VTLREEAAGA YAPLTADGTI LINRVLASCY
360 370 380 390 400
AVIEEHSWAH RAFAPFRLAH ALLAALAPAR TDGGGGGSIP APQSVAEARG
410 420 430
AGPPAGIHWY SQLLYHIGTW LLDSETLHPL GMAVKSS
Length:437
Mass (Da):47,630
Last modified:November 1, 1996 - v1
Checksum:i0DBFC19F0D1662A0
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L27340 mRNA. Translation: AAA20999.1.
PIRiB53193.
RefSeqiNP_058917.1. NM_017221.1.
UniGeneiRn.10432.

Genome annotation databases

GeneIDi29499.
KEGGirno:29499.

Similar proteinsi

Entry informationi

Entry nameiSHH_RAT
AccessioniPrimary (citable) accession number: Q63673
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: November 1, 1996
Last modified: November 22, 2017
This is version 152 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families