UniProt ID: Q92008 |
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). {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7583153}. FUNCTION: [Sonic hedgehog protein A 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 (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). In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (By similarity). {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7583153}. CATALYTIC ACTIVITY: [Sonic hedgehog protein]: Reaction=cholesterol + glycyl-L-cysteinyl-[protein] + H(+) = [protein]- C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl- [protein]; Xref=Rhea:RHEA:59504, Rhea:RHEA-COMP:12707, Rhea:RHEA- COMP:15369, Rhea:RHEA-COMP:15374, ChEBI:CHEBI:15378, ChEBI:CHEBI:16113, ChEBI:CHEBI:65250, ChEBI:CHEBI:143135, ChEBI:CHEBI:143140; Evidence={ECO:0000250|UniProtKB:Q62226}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505; Evidence={ECO:0000250|UniProtKB:Q62226}; 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). {ECO:0000250|UniProtKB:Q15465, ECO:0000250|UniProtKB:Q62226}. SUBUNIT: [Sonic hedgehog protein A N-product]: Multimer. {ECO:0000250|UniProtKB:Q15465}. SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q15465}. Note=Co-localizes with HHAT in the ER and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}. SUBCELLULAR LOCATION: [Sonic hedgehog protein A N-product]: Cell membrane {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor {ECO:0000250|UniProtKB:Q62226}. 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. {ECO:0000250|UniProtKB:Q62226}. TISSUE SPECIFICITY: Expressed in the ventral midline of the neural tube and brain. Also found in the notochord and in developing fin bud. In the developing brain, expression occurs in domains that include a discrete region in the floor of the diencephalon. DEVELOPMENTAL STAGE: First detectable in the inner cell layer of the embryonic shield during gastrulation. By 9.5 hours of development, expressed in a continuous band that extends from the tail to the head, the anterior boundary of expression being positioned in the center of the animal pole anterior to the presumptive midbrain. DOMAIN: [Sonic hedgehog protein A N-product]: Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein- protein interactions mediated by this domain. {ECO:0000250|UniProtKB:Q62226}. DOMAIN: [Sonic hedgehog protein A 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). {ECO:0000250|UniProtKB:Q62226}. PTM: [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). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:7583153}. PTM: [Sonic hedgehog protein A 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). {ECO:0000250|UniProtKB:Q62226}. PTM: [Sonic hedgehog protein A 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). {ECO:0000250|UniProtKB:Q62226}. SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}. CAUTION: The several steps and mechanisms that permit controlled Shh dispersion and gradient formation remain controversial. The Shh 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. {ECO:0000250|UniProtKB:Q62226}. |
UniProt ID: Q1MTB5 |
FUNCTION: [Protein hedgehog N-product]: The dually lipidated hedgehog protein N-product is a morphogen which is essential for a variety of patterning events during development. {ECO:0000256|RuleBase:RU280812}. FUNCTION: [Protein hedgehog]: The C-terminal part of the hedgehog protein precursor displays an autoproteolysis activity that results in the cleavage of the full-length protein into two parts (N-product and C-product). In addition, the C-terminal part displays a cholesterol transferase activity that results by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product. {ECO:0000256|RuleBase:RU280812}. CATALYTIC ACTIVITY: Reaction=cholesterol + glycyl-L-cysteinyl-[protein] + H(+) = [protein]- C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl- [protein]; Xref=Rhea:RHEA:59504, Rhea:RHEA-COMP:12707, Rhea:RHEA- COMP:15369, Rhea:RHEA-COMP:15374, ChEBI:CHEBI:15378, ChEBI:CHEBI:16113, ChEBI:CHEBI:65250, ChEBI:CHEBI:143135, ChEBI:CHEBI:143140; Evidence={ECO:0000256|ARBA:ARBA00034065}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505; Evidence={ECO:0000256|ARBA:ARBA00034065}; SUBUNIT: Multimer. {ECO:0000256|ARBA:ARBA00034131}. SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000256|ARBA:ARBA00004586}. Membrane {ECO:0000256|ARBA:ARBA00004635}; Lipid-anchor {ECO:0000256|ARBA:ARBA00004635}. SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum membrane {ECO:0000256|RuleBase:RU280812}. Golgi apparatus membrane {ECO:0000256|RuleBase:RU280812}. SUBCELLULAR LOCATION: [Protein hedgehog N-product]: Cell membrane {ECO:0000256|RuleBase:RU280812}; Lipid-anchor {ECO:0000256|RuleBase:RU280812}. SIMILARITY: Belongs to the hedgehog family. {ECO:0000256|ARBA:ARBA00010649, ECO:0000256|RuleBase:RU280812}. |
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