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Details on Person UniProt:Q15465 SHH
| Class:Id | ReferenceGeneProduct:64432 |
|---|---|
| _chainChangeLog | signal peptide:1-23 added on Sat February 7 2015;chain:24-462 added on Sat February 7 2015;chain:24-197 added on Sat February 7 2015;chain:198-462 added on Sat February 7 2015 |
| _displayName | UniProt:Q15465 SHH |
| _timestamp | 2025-02-21 19:22:52 |
| chain | signal peptide:1-23 chain:24-462 chain:24-197 |
| checksum | DD687AFA582A4749 |
| comment | FUNCTION 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 endoplasmic reticulum (By similarity). Once cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).FUNCTION 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 (PubMed:24863049). 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 (PubMed:10753901). In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (PubMed:10753901).CATALYTIC ACTIVITY glycyl-L-cysteinyl-[protein] + cholesterol + H(+) = [protein]-C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-[protein]SUBUNIT Multimer.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 (PubMed:19561609). Interacts with DISP1 via its cholesterol anchor (PubMed:22677548, PubMed:22902404). Interacts with SCUBE2 (PubMed:22677548, PubMed:24522195). Interacts with glypican GPC3 (By similarity).INTERACTION Co-localizes with HHAT in the ER and Golgi membrane.SUBCELLULAR LOCATION The dual-lipidated sonic hedgehog protein N-product (ShhNp) is firmly tethered to the cell membrane where it forms multimers (PubMed:24522195). 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 (PubMed:24522195, PubMed:26875496).DOMAIN Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.DOMAIN The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized ShhNp (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at the heparan sulfate-binding Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).PTM 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 (PubMed:24522195, PubMed:26875496). ShhN is the active species in both local and long-range signaling, whereas the C-product (ShhC) is degraded in the endoplasmic reticulum (By similarity).PTM 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 (PubMed:24522195).PTM The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding) (PubMed:24522195). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (PubMed:23118222, PubMed:24522195).MASS SPECTROMETRY Sonic hedgehog protein N-product: soluble product, purified from insect cells.MASS SPECTROMETRY Sonic hedgehog protein N-product: Membrane-bound product, purified from insect cells.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The gene represented in this entry is involved in disease pathogenesis. SHH expression is altered due to disease-causing variants located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH.DISEASE The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695).DISEASE The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences.DISEASE The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159).SIMILARITY Belongs to the hedgehog family.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 (PubMed:26875496). Once released, the fully processed Shh can signal within embryonic tissues both at short and long-range. |
| description | recommendedName: fullName evidence="41"Sonic hedgehog protein shortName: SHH ecNumber evidence="2"3.1.-.- alternativeName: HHG-1 alternativeName: fullName evidence="38"Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains shortName evidence="38"ShhNC component recommendedName: Sonic hedgehog protein N-product shortName: ShhN alternativeName: fullName evidence="38"Shh N-terminal processed signaling domains shortName evidence="38"ShhNp /component |
| geneName | SHH |
| identifier | Q15465 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Autocatalytic cleavage Calcium Cell membrane Developmental protein Direct protein sequencing Disease variant Endoplasmic reticulum Glycoprotein Golgi apparatus Holoprosencephaly Hydrolase Lipoprotein Membrane Metal-binding Microphthalmia Palmitate Protease Proteomics identification Reference proteome Secreted Signal Transferase Zinc |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 |
| name | SHH |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:9003232] ENSEMBL:ENSG00000164690 SHH [Homo sapiens] |
| secondaryIdentifier | SHH_HUMAN A4D247 Q75MC9 |
| sequenceLength | 462 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:445140] CHOL-N-palmitoyl-L-cysteine-SHH(24-197) [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:5358280] 2xHC-SHH(24-462) [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358289] N4glycoAsn-SHH(198-462) [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358296] CHOL-SHH(24-197) [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358315] N4glycoAsn-HC-SHH(24-462) [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358401] SHH(24-462) W117R [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358404] SHH(24-462) W117G [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358425] SHH(24-462) R381P [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358427] SHH(24-462) P377S [endoplasmic reticulum lumen] [Homo sapiens] [EntityWithAccessionedSequence:5358428] SHH(24-462) L382P [endoplasmic reticulum lumen] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:445137] glycine cholesterol ester at 197 [ModifiedResidue:445428] N-palmitoyl-L-cysteine at 24 [IntraChainCrosslinkedResidue:5358281] Intra-chain Crosslink via L-cystine (cross-link) at 198 and 363 [InterChainCrosslinkedResidue:5358304] Inter-chain Crosslink via L-cystine (cross-link) at 363 and 53 [ReplacedResidue:5358402] L-tryptophan 117 replaced with L-arginine [ReplacedResidue:5358405] L-tryptophan 117 replaced with glycine [ReplacedResidue:5358406] L-proline 377 replaced with L-serine [ReplacedResidue:5358408] L-leucine 382 replaced with L-proline [ReplacedResidue:5358411] L-histidine 374 replaced with L-arginine [ReplacedResidue:5358413] L-cysteine 198 replaced with L-serine |
| (secondReferenceSequence) | [InterChainCrosslinkedResidue:5358303] Inter-chain Crosslink via L-cystine (cross-link) at 53 and 363 |
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No pathways have been reviewed or authored by UniProt:Q15465 SHH (64432)
