Q90385 · SHH_CYNPY

Function

function

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).

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).

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.

Catalytic activity

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
Site246Involved in cholesterol transfer
Site268Involved in auto-cleavage
Site271Essential for auto-cleavage

GO annotations

AspectTerm
Cellular Componentendoplasmic reticulum membrane
Cellular ComponentGolgi membrane
Cellular Componentplasma membrane
Molecular Functioncholesterol-protein transferase activity
Molecular Functionmetal ion binding
Molecular Functionpeptidase activity
Biological Processanimal organ development
Biological Processcell development
Biological Processcell fate commitment
Biological Processcell-cell signaling
Biological Processcentral nervous system development
Biological Processintein-mediated protein splicing
Biological Processneuron differentiation
Biological Processpattern specification process
Biological Processpositive regulation of smoothened signaling pathway
Biological Processprotein autoprocessing
Biological Processregulation of cell population proliferation
Biological Processregulation of developmental process
Biological Processself proteolysis
Biological Processtissue development
Biological Processtube development

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

  • Recommended name
    Sonic hedgehog protein
  • EC number
  • Short names
    SHH
  • Cleaved into 1 chains

Gene names

    • Name
      SHH

Organism names

Accessions

  • Primary accession
    Q90385

Subcellular Location

Sonic hedgehog protein

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

Sonic hedgehog protein N-product

Cell membrane
; Lipid-anchor
Note: The dual-lipidated sonic hedgehog protein N-product (ShhNp) 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

Keywords

PTM/Processing

Features

Showing features for signal, lipidation, chain.

TypeIDPosition(s)Description
Signal1-26
Lipidation27N-palmitoyl cysteine
ChainPRO_000001322427-200Sonic hedgehog protein N-product
ChainPRO_000001322327-432Sonic hedgehog protein
Lipidation200Cholesterol glycine ester

Post-translational modification

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).

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).

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).

Keywords

Expression

Induction

Activated by activin, basic fibroblast growth factor (BFGF) and fork head.

Interaction

Subunit

Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH 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).

Sonic hedgehog protein N-product

Multimer.

Structure

Family & Domains

Features

Showing features for motif.

TypeIDPosition(s)Description
Motif35-41Cardin-Weintraub

Domain

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.

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).

Sequence similarities

Belongs to the hedgehog family.

Keywords

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    432
  • Mass (Da)
    47,847
  • Last updated
    1996-11-01 v1
  • Checksum
    B455C7E746C8E5A8
MDEMILLRRVLLAGFICALLVPSGLSCGPGRGIGTRKRFKKLTPLAYKQFTPNVPEKTLGASGRYEGKITRNSERFKELTPNYNPDIIFKDEENTGADRLMTQRCKDKLNALAISVMNQWPGVKLRVTEGWDEDGHHFEESLHYEGRAVDITTSDRDRSKYGMLARLAAEAGFDWVYFESKAHIHCSVKAENSVAAKSGGCFPGSATVALEQGVRIPVKDLRPGDRVLAADGLGKLVYSDFLLFMDKEETVRKVFYVIETSRERVRLTAAHLLFVGQAHPGNDSGGDFRSVFGSAGFRSMFASSVRAGHRVLTVDREGRGLREATVERVYLEEATGAYAPVTAHGTVVIDRVLASCYAVIEEHSWAHWAFAPLRVGLGILSFFSPQDYSSHSPPAPSQSEGVHWYSEILYRIGTWVLQEDTIHPLGMAAKSS

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
D63339
EMBL· GenBank· DDBJ
BAA09657.1
EMBL· GenBank· DDBJ
mRNA

Similar Proteins

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