TWHH_DANRE
ID TWHH_DANRE Reviewed; 416 AA.
AC Q90419; O13212;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Tiggy-winkle hedgehog protein {ECO:0000305};
DE Short=TWHH;
DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=Sonic hedgehog protein B;
DE Short=SHHB;
DE Contains:
DE RecName: Full=Tiggy-winkle hedgehog protein N-product;
DE AltName: Full=Shh N-terminal processed signaling domains {ECO:0000250|UniProtKB:Q62226};
DE Short=ShhNp {ECO:0000250|UniProtKB:Q62226};
DE AltName: Full=Sonic hedgehog protein N-product;
DE Short=ShhN;
DE Flags: Precursor;
GN Name=shhb; Synonyms=twhh;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEOLYTIC PROCESSING, AUTOCATALYTIC CLEAVAGE,
RP TISSUE SPECIFICITY, FUNCTION, AND MUTAGENESIS OF HIS-273.
RC TISSUE=Embryo;
RX PubMed=7583153; DOI=10.1016/s0960-9822(95)00185-0;
RA Ekker S.C., Ungar A.R., Greenstein P., von Kessler D.P., Porter J.A.,
RA Moon R.T., Beachy P.A.;
RT "Patterning activities of vertebrate hedgehog proteins in the developing
RT eye and brain.";
RL Curr. Biol. 5:944-955(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 110-162.
RC TISSUE=Muscle;
RX PubMed=8917540; DOI=10.1073/pnas.93.23.13036;
RA Zardoya R., Abouheif E., Meyer A.;
RT "Evolutionary analyses of hedgehog and Hoxd-10 genes in fish species
RT closely related to the zebrafish.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:13036-13041(1996).
CC -!- FUNCTION: [Tiggy-winkle hedgehog protein]: The C-terminal part of the
CC tiggy-winkle hedgehog protein precursor displays an autoproteolysis and
CC a cholesterol transferase activity (By similarity). Both activities
CC result in the cleavage of the full-length protein into two parts (N-
CC product and C-product) followed by the covalent attachment of a
CC cholesterol moiety to the C-terminal of the newly generated N-product
CC (By similarity). Both activities occur in the reticulum endoplasmic (By
CC similarity). Once cleaved, the C-product is degraded in the endoplasmic
CC reticulum (By similarity). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7583153}.
CC -!- FUNCTION: [Tiggy-winkle hedgehog protein N-product]: The dually
CC lipidated tiggy-winkle hedgehog protein N-product is a morphogen which
CC is essential for a variety of patterning events during development (By
CC similarity). Involved in dorso-ventral patterning of the brain and in
CC early patterning of the developing eyes (PubMed:7583153). Binds to the
CC patched (PTCH1) receptor, which functions in association with
CC smoothened (SMO), to activate the transcription of target genes (By
CC similarity). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7583153}.
CC -!- SUBUNIT: [Tiggy-winkle hedgehog protein N-product]: Multimer.
CC {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBUNIT: Interacts with HHATL/GUP1 which negatively regulates HHAT-
CC mediated palmitoylation of the TWHH 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 -!- SUBCELLULAR LOCATION: [Tiggy-winkle hedgehog protein N-product]: Cell
CC membrane {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q62226}. Note=The dual-lipidated tiggy-winkle
CC hedgehog protein N-product (TWHHN) is firmly tethered to the cell
CC membrane where it forms multimers (By similarity). Further
CC solubilization and release from the cell surface seem to be achieved
CC through different mechanisms, including the interaction with DISP1 and
CC SCUBE2, movement by lipoprotein particles, transport by cellular
CC extensions called cytonemes or by the proteolytic removal of both
CC terminal lipidated peptides. {ECO:0000250|UniProtKB:Q62226}.
CC -!- SUBCELLULAR LOCATION: [Tiggy-winkle hedgehog protein]: Endoplasmic
CC reticulum membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus
CC membrane {ECO:0000250|UniProtKB:Q15465}. Note=Co-localizes with HHAT in
CC the ER and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}.
CC -!- TISSUE SPECIFICITY: Expressed in the ventral midline of the neural tube
CC and brain. In the developing brain, expression occurs in domains that
CC include a discrete region in the floor of the diencephalon. Not
CC detected in the notochord or developing fin bud.
CC {ECO:0000269|PubMed:7583153}.
CC -!- DOMAIN: [Tiggy-winkle hedgehog protein N-product]: Binds calcium and
CC zinc ions; this stabilizes the protein fold and is essential for
CC protein-protein interactions mediated by this domain.
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- DOMAIN: [Tiggy-winkle hedgehog protein N-product]: The Cardin-Weintraub
CC (CW) motif is required for heparan sulfate binding of the solubilized
CC TWHHN (By similarity). The N-terminal palmitoylated peptide is cleaved
CC at the 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: [Tiggy-winkle 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 into two parts (N-product and C-product) followed by the
CC covalent attachment of a cholesterol moiety to the C-terminal of the
CC newly generated N-product (By similarity). Cholesterylation is required
CC for the tiggy-winkle hedgehog protein N-product targeting to lipid
CC rafts and multimerization (By similarity). N-product is the active
CC species in both local and long-range signaling, whereas the C-product
CC is degraded in the reticulum endoplasmic (By similarity).
CC {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7583153}.
CC -!- PTM: [Tiggy-winkle hedgehog protein N-product]: N-palmitoylation by
CC HHAT of N-product is required for tiggy-winkle hedgehog protein N-
CC product multimerization and full activity (By similarity). It is a
CC prerequisite for the membrane-proximal positioning and the subsequent
CC shedding of this N-terminal peptide (By similarity).
CC {ECO:0000250|UniProtKB:Q62226}.
CC -!- PTM: [Tiggy-winkle hedgehog protein N-product]: The lipidated N- and C-
CC terminal peptides of N-product can be cleaved (shedding) (By
CC similarity). The N-terminal palmitoylated peptide is cleaved at the
CC Cardin-Weintraub (CW) motif site (By similarity). The cleavage reduced
CC the interactions with heparan sulfate (By similarity). The cleavage is
CC enhanced by 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 tiggy-
CC winkle hedgehog dispersion and gradient formation remain controversial.
CC The C-terminal part of the tiggy-winkle hedgehog protein precursor
CC displays an autoproteolysis activity and a cholesterol transferase
CC activity resulting in the cleavage and covalent attachment of a
CC cholesterol moiety to the C-terminal of the newly generated N-terminal
CC fragment (N-product). The protein is further modified by covalent
CC addition of palmitate at the N-terminal of N-product, resulting to the
CC dual-lipidated N-product. The latter is firmly tethered to the cell
CC membrane where it forms multimers. 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 proteolytic removal of both terminal lipidated
CC peptides. Once released, the fully processed TWHHN can signal within
CC embryonic tissues both at short and long-range.
CC {ECO:0000250|UniProtKB:Q62226}.
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DR EMBL; U30710; AAC59741.1; -; mRNA.
DR EMBL; U68237; AAB38678.1; -; Genomic_DNA.
DR AlphaFoldDB; Q90419; -.
DR SMR; Q90419; -.
DR STRING; 7955.ENSDARP00000056746; -.
DR MEROPS; C46.005; -.
DR PaxDb; Q90419; -.
DR Ensembl; ENSDART00000056747; ENSDARP00000056746; ENSDARG00000038867.
DR ZFIN; ZDB-GENE-980526-41; shhb.
DR eggNOG; KOG3638; Eukaryota.
DR GeneTree; ENSGT00940000159119; -.
DR HOGENOM; CLU_034686_0_0_1; -.
DR InParanoid; Q90419; -.
DR OMA; HQVDLQS; -.
DR PhylomeDB; Q90419; -.
DR TreeFam; TF106458; -.
DR PRO; PR:Q90419; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 2.
DR Bgee; ENSDARG00000038867; Expressed in floor plate and 26 other tissues.
DR ExpressionAtlas; Q90419; baseline.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IBA:GO_Central.
DR GO; GO:0005113; F:patched binding; IBA:GO_Central.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0001708; P:cell fate specification; IBA:GO_Central.
DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro.
DR GO; GO:0048702; P:embryonic neurocranium morphogenesis; IGI:ZFIN.
DR GO; GO:0048703; P:embryonic viscerocranium morphogenesis; IGI:ZFIN.
DR GO; GO:0060956; P:endocardial cell differentiation; IGI:ZFIN.
DR GO; GO:0030900; P:forebrain development; IMP:ZFIN.
DR GO; GO:0042063; P:gliogenesis; IGI:ZFIN.
DR GO; GO:0030182; P:neuron differentiation; IMP:ZFIN.
DR GO; GO:0048663; P:neuron fate commitment; IGI:ZFIN.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IBA:GO_Central.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR GO; GO:0007224; P:smoothened signaling pathway; IBA:GO_Central.
DR GO; GO:0055002; P:striated muscle cell development; IGI:ZFIN.
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 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.
PE 1: Evidence at protein level;
KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein;
KW Endoplasmic reticulum; Golgi apparatus; Hydrolase; Lipoprotein; Membrane;
KW Metal-binding; Palmitate; Protease; Reference proteome; Signal; Zinc.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT CHAIN 27..416
FT /note="Tiggy-winkle hedgehog protein"
FT /id="PRO_0000013256"
FT CHAIN 27..200
FT /note="Tiggy-winkle hedgehog protein N-product"
FT /id="PRO_0000013257"
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 SITE 270
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250"
FT SITE 273
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000269|PubMed:7583153"
FT LIPID 27
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 200
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000250"
FT MUTAGEN 273
FT /note="H->A: Loss of autoproteolytic cleavage."
FT /evidence="ECO:0000269|PubMed:7583153"
SQ SEQUENCE 416 AA; 46576 MW; 61EC2218309CFE59 CRC64;
MDVRLHLKQF ALLCFISLLL TPCGLACGPG RGYGKRRHPK KLTPLAYKQF IPNVAEKTLG
ASGKYEGKIT RNSERFKELI PNYNPDIIFK DEENTNADRL MTKRCKDKLN SLAISVMNHW
PGVKLRVTEG WDEDGHHLEE SLHYEGRAVD ITTSDRDKSK YGMLSRLAVE AGFDWVYYES
KAHIHCSVKA ENSVAAKSGG CFPGSGTVTL GDGTRKPIKD LKVGDRVLAA DEKGNVLISD
FIMFIDHDPT TRRQFIVIET SEPFTKLTLT AAHLVFVGNS SAASGITATF ASNVKPGDTV
LVWEDTCESL KSVTVKRIYT EEHEGSFAPV TAHGTIIVDQ VLASCYAVIE NHKWAHWAFA
PVRLCHKLMT WLFPARESNV NFQEDGIHWY SNMLFHIGSW LLDRDSFHPL GILHLS
