SHH_CYNPY
ID SHH_CYNPY Reviewed; 432 AA.
AC Q90385;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Sonic hedgehog protein {ECO:0000305};
DE Short=SHH;
DE EC=3.1.-.- {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 Cynops pyrrhogaster (Japanese fire-bellied newt) (Molge pyrrhogaster).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Amphibia;
OC Batrachia; Caudata; Salamandroidea; Salamandridae; Pleurodelinae; Cynops.
OX NCBI_TaxID=8330;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION.
RC TISSUE=Embryo;
RX PubMed=8573168; DOI=10.1006/bbrc.1996.0069;
RA Takabatake T., Takahashi T.C., Inoue K., Ogawa M., Takeshima K.;
RT "Activation of two Cynops genes, fork head and sonic hedgehog, in animal
RT cap explants.";
RL Biochem. Biophys. Res. Commun. 218:395-401(1996).
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 -!- 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 (By
CC similarity). Involved in the patterning of the anterior-posterior axis
CC of the developing limb bud (By similarity). Essential for axon guidance
CC (By similarity). Binds to the patched (PTCH1) receptor, which functions
CC in association with smoothened (SMO), to activate the transcription of
CC target genes (By similarity). In the absence of SHH, PTCH1 represses
CC the constitutive signaling activity of SMO (By similarity).
CC {ECO:0000250|UniProtKB:Q15465}.
CC -!- CATALYTIC ACTIVITY:
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 -!- INDUCTION: Activated by activin, basic fibroblast growth factor (BFGF)
CC and fork head. {ECO:0000269|PubMed:8573168}.
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 -!- 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; D63339; BAA09657.1; -; mRNA.
DR AlphaFoldDB; Q90385; -.
DR SMR; Q90385; -.
DR MEROPS; C46.002; -.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0048731; P:system development; IEA:UniProt.
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 2: Evidence at transcript level;
KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein;
KW Endoplasmic reticulum; Golgi apparatus; Hydrolase; Lipoprotein; Membrane;
KW Metal-binding; Palmitate; Protease; Signal; Zinc.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT CHAIN 27..432
FT /note="Sonic hedgehog protein"
FT /id="PRO_0000013223"
FT CHAIN 27..200
FT /note="Sonic hedgehog protein N-product"
FT /id="PRO_0000013224"
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 268
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 271
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 27
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT LIPID 200
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250|UniProtKB:Q62226"
SQ SEQUENCE 432 AA; 47847 MW; B455C7E746C8E5A8 CRC64;
MDEMILLRRV LLAGFICALL VPSGLSCGPG RGIGTRKRFK KLTPLAYKQF TPNVPEKTLG
ASGRYEGKIT RNSERFKELT PNYNPDIIFK DEENTGADRL MTQRCKDKLN ALAISVMNQW
PGVKLRVTEG WDEDGHHFEE SLHYEGRAVD ITTSDRDRSK YGMLARLAAE AGFDWVYFES
KAHIHCSVKA ENSVAAKSGG CFPGSATVAL EQGVRIPVKD LRPGDRVLAA DGLGKLVYSD
FLLFMDKEET VRKVFYVIET SRERVRLTAA HLLFVGQAHP GNDSGGDFRS VFGSAGFRSM
FASSVRAGHR VLTVDREGRG LREATVERVY LEEATGAYAP VTAHGTVVID RVLASCYAVI
EEHSWAHWAF APLRVGLGIL SFFSPQDYSS HSPPAPSQSE GVHWYSEILY RIGTWVLQED
TIHPLGMAAK SS
