Q90419 · TWHH_DANRE

Function

function

Tiggy-winkle hedgehog protein

The C-terminal part of the tiggy-winkle 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 (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (By similarity).
Both activities occur in the reticulum endoplasmic (By similarity).
Once cleaved, the C-product is degraded in the endoplasmic reticulum (By similarity).

Tiggy-winkle hedgehog protein N-product

The dually lipidated tiggy-winkle hedgehog protein N-product is a morphogen which is essential for a variety of patterning events during development (By similarity).
Involved in dorso-ventral patterning of the brain and in early patterning of the developing eyes (PubMed:7583153).
Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes (By similarity).

Caution

The several steps and mechanisms that permit controlled tiggy-winkle hedgehog dispersion and gradient formation remain controversial. The C-terminal part of the tiggy-winkle hedgehog protein precursor 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 (N-product). The protein is further modified by covalent addition of palmitate at the N-terminal of N-product, resulting to the dual-lipidated N-product. The latter 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 TWHHN can signal within embryonic tissues both at short and long-range.

Features

Showing features for binding site, site.

TypeIDPosition(s)Description
Binding site92Ca2+ 1 (UniProtKB | ChEBI)
Binding site93Ca2+ 1 (UniProtKB | ChEBI)
Binding site93Ca2+ 2 (UniProtKB | ChEBI)
Binding site98Ca2+ 1 (UniProtKB | ChEBI)
Binding site128Ca2+ 1 (UniProtKB | ChEBI)
Binding site129Ca2+ 1 (UniProtKB | ChEBI)
Binding site129Ca2+ 2 (UniProtKB | ChEBI)
Binding site132Ca2+ 2 (UniProtKB | ChEBI)
Binding site134Ca2+ 2 (UniProtKB | ChEBI)
Binding site143Zn2+ (UniProtKB | ChEBI)
Binding site150Zn2+ (UniProtKB | ChEBI)
Binding site185Zn2+ (UniProtKB | ChEBI)
Site200-201Cleavage; by autolysis
Site270Involved in auto-cleavage
Site273Essential for auto-cleavage

GO annotations

AspectTerm
Cellular Componentendoplasmic reticulum membrane
Cellular Componentextracellular space
Cellular ComponentGolgi membrane
Cellular Componentplasma membrane
Molecular Functioncalcium ion binding
Molecular Functioncholesterol-protein transferase activity
Molecular Functionpatched binding
Molecular Functionpeptidase activity
Biological Processcell fate specification
Biological Processcell-cell signaling
Biological Processembryonic neurocranium morphogenesis
Biological Processembryonic viscerocranium morphogenesis
Biological Processendocardial cell differentiation
Biological Processforebrain development
Biological Processgliogenesis
Biological Processneuron differentiation
Biological Processneuron fate commitment
Biological Processoligodendrocyte differentiation
Biological Processpositive regulation of smoothened signaling pathway
Biological Processprotein autoprocessing
Biological Processregulation of gene expression
Biological Processself proteolysis
Biological Processsmoothened signaling pathway
Biological Processstriated muscle cell development

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

  • Recommended name
    Tiggy-winkle hedgehog protein
  • EC number
  • Short names
    TWHH
  • Alternative names
    • Sonic hedgehog protein B (SHHB)
  • Cleaved into 1 chains

Gene names

    • Name
      shhb
    • Synonyms
      twhh

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Actinopterygii > Neopterygii > Teleostei > Ostariophysi > Cypriniformes > Danionidae > Danioninae > Danio

Accessions

  • Primary accession
    Q90419
  • Secondary accessions
    • O13212

Proteomes

Organism-specific databases

Subcellular Location

Tiggy-winkle hedgehog protein N-product

Cell membrane
; Lipid-anchor
Note: The dual-lipidated tiggy-winkle hedgehog protein N-product (TWHHN) is firmly tethered to the cell membrane where it forms multimers (By similarity).
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 the proteolytic removal of both terminal lipidated peptides

Tiggy-winkle hedgehog protein

Note: Co-localizes with HHAT in the ER and Golgi membrane.

Keywords

Phenotypes & Variants

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis273Loss of autoproteolytic cleavage.

PTM/Processing

Features

Showing features for signal, lipidation, chain.

TypeIDPosition(s)Description
Signal1-26
Lipidation27N-palmitoyl cysteine
ChainPRO_000001325727-200Tiggy-winkle hedgehog protein N-product
ChainPRO_000001325627-416Tiggy-winkle hedgehog protein
Lipidation200Cholesterol glycine ester

Post-translational modification

Tiggy-winkle 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 into two parts (N-product and C-product) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product (By similarity).
Cholesterylation is required for the tiggy-winkle hedgehog protein N-product targeting to lipid rafts and multimerization (By similarity).
N-product is the active species in both local and long-range signaling, whereas the C-product is degraded in the reticulum endoplasmic (By similarity).

Tiggy-winkle hedgehog protein N-product

N-palmitoylation by HHAT of N-product is required for tiggy-winkle 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).

Tiggy-winkle hedgehog protein N-product

The lipidated N- and C-terminal peptides of N-product 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).

Keywords

Proteomic databases

Expression

Tissue specificity

Expressed in the ventral midline of the neural tube and brain. In the developing brain, expression occurs in domains that include a discrete region in the floor of the diencephalon. Not detected in the notochord or developing fin bud.

Gene expression databases

Interaction

Subunit

Tiggy-winkle hedgehog protein N-product

Multimer.
Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the TWHH N-terminus (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).

Protein-protein interaction databases

Structure

Family & Domains

Domain

Tiggy-winkle 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.

Tiggy-winkle hedgehog protein N-product

The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized TWHHN (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).

Sequence similarities

Belongs to the hedgehog family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    416
  • Mass (Da)
    46,576
  • Last updated
    1996-11-01 v1
  • Checksum
    61EC2218309CFE59
MDVRLHLKQFALLCFISLLLTPCGLACGPGRGYGKRRHPKKLTPLAYKQFIPNVAEKTLGASGKYEGKITRNSERFKELIPNYNPDIIFKDEENTNADRLMTKRCKDKLNSLAISVMNHWPGVKLRVTEGWDEDGHHLEESLHYEGRAVDITTSDRDKSKYGMLSRLAVEAGFDWVYYESKAHIHCSVKAENSVAAKSGGCFPGSGTVTLGDGTRKPIKDLKVGDRVLAADEKGNVLISDFIMFIDHDPTTRRQFIVIETSEPFTKLTLTAAHLVFVGNSSAASGITATFASNVKPGDTVLVWEDTCESLKSVTVKRIYTEEHEGSFAPVTAHGTIIVDQVLASCYAVIENHKWAHWAFAPVRLCHKLMTWLFPARESNVNFQEDGIHWYSNMLFHIGSWLLDRDSFHPLGILHLS

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
Q6DBX7Q6DBX7_DANREshhb416

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
U30710
EMBL· GenBank· DDBJ
AAC59741.1
EMBL· GenBank· DDBJ
mRNA
U68237
EMBL· GenBank· DDBJ
AAB38678.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

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