SHH_CHICK
ID SHH_CHICK Reviewed; 425 AA.
AC Q91035;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Sonic hedgehog protein {ECO:0000305};
DE Short=SHH;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains {ECO:0000250|UniProtKB:Q62226};
DE Short=ShhNC {ECO:0000250|UniProtKB:Q62226};
DE Contains:
DE RecName: Full=Sonic hedgehog protein N-product;
DE Short=ShhN;
DE AltName: Full=Shh N-terminal processed signaling domains {ECO:0000250|UniProtKB:Q62226};
DE Short=ShhNp {ECO:0000250|UniProtKB:Q62226};
DE Flags: Precursor;
GN Name=SHH {ECO:0000250|UniProtKB:Q15465};
OS Gallus gallus (Chicken).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda;
OC Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae;
OC Phasianinae; Gallus.
OX NCBI_TaxID=9031;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Limb bud;
RX PubMed=8269518; DOI=10.1016/0092-8674(93)90626-2;
RA Riddle R.D., Johnson R.L., Laufer E., Tabin C.;
RT "Sonic hedgehog mediates the polarizing activity of the ZPA.";
RL Cell 75:1401-1416(1993).
RN [2]
RP FUNCTION, PROTEOLYTIC PROCESSING, AND AUTOCATALYTIC CLEAVAGE.
RX PubMed=7736596; DOI=10.1016/0092-8674(95)90397-6;
RA Roelink H., Porter J.A., Chiang C., Tanabe Y., Chang D.T., Beachy P.A.,
RA Jessell T.M.;
RT "Floor plate and motor neuron induction by different concentrations of the
RT amino-terminal cleavage product of sonic hedgehog autoproteolysis.";
RL Cell 81:445-455(1995).
RN [3]
RP GLYCOSYLATION.
RX PubMed=7891723; DOI=10.1128/mcb.15.4.2294;
RA Bumcrot D.A., Takada R., McMahon A.P.;
RT "Proteolytic processing yields two secreted forms of sonic hedgehog.";
RL Mol. Cell. Biol. 15:2294-2303(1995).
CC -!- FUNCTION: [Sonic hedgehog protein]: The C-terminal part of the sonic
CC hedgehog protein precursor displays an autoproteolysis and a
CC cholesterol transferase activity (By similarity). Both activities
CC result in the cleavage of the full-length protein into two parts (ShhN
CC and ShhC) followed by the covalent attachment of a cholesterol moiety
CC to the C-terminal of the newly generated ShhN (By similarity). Both
CC activities occur in the reticulum endoplasmic (By similarity). Once
CC cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).
CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226,
CC ECO:0000269|PubMed:7736596}.
CC -!- FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated
CC sonic hedgehog protein N-product (ShhNp) is a morphogen which is
CC essential for a variety of patterning events during development.
CC Induces ventral cell fate in the neural tube and somites
CC (PubMed:7736596). Involved in the patterning of the anterior-posterior
CC axis of the developing limb bud (By similarity). Essential for axon
CC guidance (By similarity). Binds to the patched (PTCH1) receptor, which
CC functions in association with smoothened (SMO), to activate the
CC transcription of target genes (By similarity). In the absence of SHH,
CC PTCH1 represses the constitutive signaling activity of SMO (By
CC similarity). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7736596}.
CC -!- CATALYTIC ACTIVITY: [Sonic hedgehog protein]:
CC Reaction=cholesterol + glycyl-L-cysteinyl-[protein] + H(+) = [protein]-
CC C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-
CC [protein]; Xref=Rhea:RHEA:59504, Rhea:RHEA-COMP:12707, Rhea:RHEA-
CC COMP:15369, Rhea:RHEA-COMP:15374, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:65250, ChEBI:CHEBI:143135,
CC ChEBI:CHEBI:143140; Evidence={ECO:0000250|UniProtKB:Q62226};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505;
CC Evidence={ECO:0000250|UniProtKB:Q62226};
CC -!- SUBUNIT: Interacts with HHATL/GUP1 which negatively regulates HHAT-
CC mediated palmitoylation of the SHH N-terminus (By similarity).
CC Interacts with BOC and CDON (By similarity). Interacts with HHIP (By
CC similarity). Interacts with DISP1 via its cholesterol anchor (By
CC similarity). Interacts with SCUBE2 (By similarity).
CC {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226}.
CC -!- SUBUNIT: [Sonic hedgehog protein N-product]: Multimer.
CC {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum
CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q15465}. Note=Co-localizes with HHAT in the ER
CC and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein N-product]: Cell membrane
CC {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q62226}. Note=The dual-lipidated sonic hedgehog
CC protein N-product (ShhNp) is firmly tethered to the cell membrane where
CC it forms multimers (By similarity). Further solubilization and release
CC from the cell surface seem to be achieved through different mechanisms,
CC including the interaction with DISP1 and SCUBE2, movement by
CC lipoprotein particles, transport by cellular extensions called
CC cytonemes or by the proteolytic removal of both terminal lipidated
CC peptides. {ECO:0000250|UniProtKB:Q62226}.
CC -!- TISSUE SPECIFICITY: Expressed in the posterior limb bud mesenchyme, the
CC Hensen node, the notochord, and the floor plate of the neural tube.
CC -!- DEVELOPMENTAL STAGE: First detectable at stage 17 during the initiation
CC of limb bud formation. From that point onwards, the expression pattern
CC exactly matches the location of the zone of polarizing activity (ZPA).
CC -!- INDUCTION: By retinoic acid.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: Binds calcium and zinc
CC ions; this stabilizes the protein fold and is essential for protein-
CC protein interactions mediated by this domain.
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: The Cardin-Weintraub (CW)
CC motif is required for heparan sulfate binding of the solubilized ShhNp
CC (By similarity). The N-terminal palmitoylated peptide is cleaved at the
CC Heparan sulfate-binding Cardin-Weintraub (CW) motif site (By
CC similarity). The cleavage reduced the interactions with heparan
CC sulfate. The cleavage is enhanced by SCUBE2 (By similarity).
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- PTM: [Sonic hedgehog protein]: The C-terminal domain displays an
CC autoproteolysis activity and a cholesterol transferase activity (By
CC similarity). Both activities result in the cleavage of the full-length
CC protein and covalent attachment of a cholesterol moiety to the C-
CC terminal of the newly generated N-terminal fragment (ShhN) (By
CC similarity). Cholesterylation is required for the sonic hedgehog
CC protein N-product targeting to lipid rafts and multimerization (By
CC similarity). ShhN is the active species in both local and long-range
CC signaling, whereas the C-product (ShhC) is degraded in the reticulum
CC endoplasmic (By similarity). {ECO:0000250|UniProtKB:Q62226,
CC ECO:0000269|PubMed:7736596}.
CC -!- PTM: [Sonic hedgehog protein N-product]: N-palmitoylation by HHAT of
CC ShhN is required for sonic hedgehog protein N-product multimerization
CC and full activity (By similarity). It is a prerequisite for the
CC membrane-proximal positioning and the subsequent shedding of this N-
CC terminal peptide (By similarity). {ECO:0000250|UniProtKB:Q62226}.
CC -!- PTM: [Sonic hedgehog protein N-product]: The lipidated N- and C-
CC terminal peptides of ShhNp can be cleaved (shedding) (By similarity).
CC The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub
CC (CW) motif site (By similarity). The cleavage reduced the interactions
CC with heparan sulfate (By similarity). The cleavage is enhanced by
CC SCUBE2 (By similarity). {ECO:0000250|UniProtKB:Q62226}.
CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
CC -!- CAUTION: The several steps and mechanisms that permit controlled Shh
CC dispersion and gradient formation remain controversial. The ShhNC C-
CC terminal domain displays an autoproteolysis activity and a cholesterol
CC transferase activity resulting in the cleavage and covalent attachment
CC of a cholesterol moiety to the C-terminal of the newly generated N-
CC terminal fragment (ShhN). The protein is further modified by covalent
CC addition of palmitate at the N-terminal of ShhN, resulting to the dual-
CC lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane
CC where it forms multimers. Further solubilization and release from the
CC cell surface seem to be achieved through different mechanisms,
CC including the interaction with DISP1 and SCUBE2, movement by
CC lipoprotein particles, transport by cellular extensions called
CC cytonemes or by proteolytic removal of both terminal lipidated
CC peptides. Once released, the fully processed Shh can signal within
CC embryonic tissues both at short and long-range.
CC {ECO:0000250|UniProtKB:Q62226}.
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DR EMBL; L28099; AAA72428.1; -; mRNA.
DR PIR; A49424; A49424.
DR RefSeq; NP_990152.1; NM_204821.1.
DR AlphaFoldDB; Q91035; -.
DR SMR; Q91035; -.
DR STRING; 9031.ENSGALP00000010292; -.
DR MEROPS; C46.002; -.
DR PaxDb; Q91035; -.
DR GeneID; 395615; -.
DR KEGG; gga:395615; -.
DR CTD; 6469; -.
DR VEuPathDB; HostDB:geneid_395615; -.
DR eggNOG; KOG3638; Eukaryota.
DR InParanoid; Q91035; -.
DR OrthoDB; 1169356at2759; -.
DR PhylomeDB; Q91035; -.
DR PRO; PR:Q91035; -.
DR Proteomes; UP000000539; Unplaced.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; NAS:Roslin.
DR GO; GO:0005615; C:extracellular space; IDA:AgBase.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0016015; F:morphogen activity; NAS:Roslin.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IDA:Roslin.
DR GO; GO:0097190; P:apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0001709; P:cell fate determination; NAS:AgBase.
DR GO; GO:0060573; P:cell fate specification involved in pattern specification; TAS:AgBase.
DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR GO; GO:0060591; P:chondroblast differentiation; IMP:AgBase.
DR GO; GO:0071679; P:commissural neuron axon guidance; IMP:AgBase.
DR GO; GO:0042733; P:embryonic digit morphogenesis; ISS:UniProtKB.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IDA:Roslin.
DR GO; GO:0009880; P:embryonic pattern specification; IMP:AgBase.
DR GO; GO:0060059; P:embryonic retina morphogenesis in camera-type eye; IMP:AgBase.
DR GO; GO:0090269; P:fibroblast growth factor production; IDA:AgBase.
DR GO; GO:0021508; P:floor plate formation; IMP:AgBase.
DR GO; GO:0003430; P:growth plate cartilage chondrocyte growth; IMP:AgBase.
DR GO; GO:0048877; P:homeostasis of number of retina cells; IMP:AgBase.
DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IMP:AgBase.
DR GO; GO:0003408; P:optic cup formation involved in camera-type eye development; IMP:AgBase.
DR GO; GO:0021631; P:optic nerve morphogenesis; IMP:AgBase.
DR GO; GO:0009949; P:polarity specification of anterior/posterior axis; ISS:UniProtKB.
DR GO; GO:0009951; P:polarity specification of dorsal/ventral axis; NAS:AgBase.
DR GO; GO:0010694; P:positive regulation of alkaline phosphatase activity; IDA:AgBase.
DR GO; GO:0010770; P:positive regulation of cell morphogenesis involved in differentiation; IMP:AgBase.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:AgBase.
DR GO; GO:0061075; P:positive regulation of neural retina development; IMP:AgBase.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IDA:AgBase.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; ISS:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0030166; P:proteoglycan biosynthetic process; IMP:AgBase.
DR GO; GO:0060785; P:regulation of apoptosis involved in tissue homeostasis; IMP:AgBase.
DR GO; GO:0060786; P:regulation of cell differentiation involved in tissue homeostasis; TAS:AgBase.
DR GO; GO:0010468; P:regulation of gene expression; IMP:AgBase.
DR GO; GO:2000177; P:regulation of neural precursor cell proliferation; IMP:AgBase.
DR GO; GO:0032526; P:response to retinoic acid; IDA:Roslin.
DR GO; GO:0001895; P:retina homeostasis; IMP:AgBase.
DR GO; GO:0003406; P:retinal pigment epithelium development; IMP:AgBase.
DR GO; GO:0097264; P:self proteolysis; IDA:AgBase.
DR GO; GO:0023052; P:signaling; IMP:AgBase.
DR GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IMP:AgBase.
DR GO; GO:0009888; P:tissue development; IMP:AgBase.
DR Gene3D; 3.30.1380.10; -; 1.
DR InterPro; IPR001657; Hedgehog.
DR InterPro; IPR001767; Hedgehog_Hint.
DR InterPro; IPR009045; Hedgehog_sig/DD-Pept_Zn-bd_sf.
DR InterPro; IPR000320; Hedgehog_signalling_dom.
DR InterPro; IPR003586; Hint_dom_C.
DR InterPro; IPR003587; Hint_dom_N.
DR InterPro; IPR036844; Hint_dom_sf.
DR InterPro; IPR006141; Intein_N.
DR Pfam; PF01085; HH_signal; 1.
DR Pfam; PF01079; Hint; 1.
DR PIRSF; PIRSF009400; Peptidase_C46; 1.
DR PRINTS; PR00632; SONICHHOG.
DR SMART; SM00305; HintC; 1.
DR SMART; SM00306; HintN; 1.
DR SUPFAM; SSF51294; SSF51294; 1.
DR SUPFAM; SSF55166; SSF55166; 1.
DR PROSITE; PS50817; INTEIN_N_TER; 1.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein;
KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Hydrolase;
KW Lipoprotein; Membrane; Metal-binding; Palmitate; Protease;
KW Reference proteome; Signal; Zinc.
FT SIGNAL 1..26
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT CHAIN 27..425
FT /note="Sonic hedgehog protein"
FT /id="PRO_0000013217"
FT CHAIN 27..200
FT /note="Sonic hedgehog protein N-product"
FT /id="PRO_0000013218"
FT MOTIF 35..41
FT /note="Cardin-Weintraub"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
FT BINDING 92
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 93
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 93
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 98
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 128
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 129
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 129
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 134
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 143
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 150
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT BINDING 185
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT SITE 200..201
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 246
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 270
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 273
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 27
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 200
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
FT CARBOHYD 282
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 425 AA; 46474 MW; DA9627443D4A0173 CRC64;
MVEMLLLTRI LLVGFICALL VSSGLTCGPG RGIGKRRHPK KLTPLAYKQF IPNVAEKTLG
ASGRYEGKIT RNSERFKELT PNYNPDIIFK DEENTGADRL MTQRCKDKLN ALAISVMNQW
PGVKLRVTEG WDEDGHHSEE SLHYEGRAVD ITTSDRDRSK YGMLARLAVE AGFDWVYYES
KAHIHCSVKA ENSVAAKSGG CFPGSATVHL EHGGTKLVKD LSPGDRVLAA DADGRLLYSD
FLTFLDRMDS SRKLFYVIET RQPRARLLLT AAHLLFVAPQ HNQSEATGST SGQALFASNV
KPGQRVYVLG EGGQQLLPAS VHSVSLREEA SGAYAPLTAQ GTILINRVLA SCYAVIEEHS
WAHWAFAPFR LAQGLLAALC PDGAIPTAAT TTTGIHWYSR LLYRIGSWVL DGDALHPLGM
VAPAS
