Shh
entrez
20423
canonical
uniprot
Q62226
canonical
ensembl
ENSMUSG00000002633
resolver
ensp
ENSMUSP00000002708
resolver
enst
ENSMUST00000002708
resolver
genesymbol
Shh
resolver
genesymbol_syn
Hhg1
resolver
uniprot_entry
SHH_MOUSE
resolver
amino_acid_sequence
MLLLLARCFLVILASSLLVCPGLACGPGRGFGKRRHPKKLTPLAYKQFIPNVAEKTLGASGRYEGKITRNSERFKELTPNYNPDIIFKDEENTGADRLMTQRCKDKLNALAISVMNQWPGVKLRVTEGWDEDGHHSEESLHYEGRAVDITTSDRDRSKYGMLARLAVEAGFDWVYYESKAHIHCSVKAENSVAAKSGGCFPGSATVHLEQGGTKLVKDLRPGDRVLAADDQGRLLYSDFLTFLDRDEGAKKVFYVIETLEPRERLLLTAAHLLFVAPHNDSGPTPGPSALFASRVRPGQRVYVVAERGGDRRLLPAAVHSVTLREEEAGAYAPLTAHGTILINRVLASCYAVIEEHSWAHRAFAPFRLAHALLAALAPARTDGGGGGSIPAAQSATEARGAEPTAGIHWYSQLLYHIGTWLLDSETMHPLGMAVKSS
uniprot
proteins
ec_number
3.1.-.-
uniprot
proteins
function
FUNCTION: [Sonic hedgehog protein]: Precursor of sonic hedgehog, a morphogen that activates the smoothened signaling pathway, and which is essential for a variety of patterning events during development (PubMed:11389830, PubMed:31657721, PubMed:7736596, PubMed:7891723, PubMed:8824192). The C-terminal part of the precursor displays an autoproteolysis and a cholesterol transferase activity, resulting (1) in the cleavage of the full-length protein into two parts, Sonic hedgehog protein N-product and C-product (ShhN and ShhC, respectively) and (2) covalent attachment of a cholesterol moiety to the C-terminus of the newly generated ShhN (PubMed:7736596, PubMed:7891723, PubMed:8824192). Both autoproteolysis and a cholesterol transferase activities occur in the endoplasmic reticulum (PubMed:21357747). Following additional lipidation, ShhN acts as a morphogen, while ShhC is degraded in the endoplasmic reticulum (PubMed:21357747). {ECO:0000269|PubMed:11389830, ECO:0000269|PubMed:21357747, ECO:0000269|PubMed:31657721, ECO:0000269|PubMed:7736596, ECO:0000269|PubMed:7891723, ECO:0000269|PubMed:8824192}.; FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated sonic hedgehog protein N-product (ShhN) is a morphogen that activates the smoothened signaling pathway, and which is essential for a variety of patterning events during development (PubMed:11389830, PubMed:14687547, PubMed:29622726, PubMed:7736596, PubMed:7916661). Acts by binding to the patched receptor (PTCH1 or PTCH2), relieving smoothened (SMO) inhibition by patched, activating the smoothened signaling pathway and transcription of target genes (PubMed:31657721). In the absence of SHH, patched represses the constitutive signaling activity of SMO (PubMed:31657721). ShhN is widely expressed and plays a key role in the patterning of the central nervous system and limb development (PubMed:11430830, PubMed:12679031, PubMed:15315762, PubMed:24863049). Induces ventral cell fate in the neural tube and somites (PubMed:11430830, PubMed:24863049). Involved in the patterning of the anterior-posterior axis of the developing limb bud (PubMed:15315762). Essential for axon guidance (PubMed:12679031). {ECO:0000269|PubMed:11389830, ECO:0000269|PubMed:11430830, ECO:0000269|PubMed:12679031, ECO:0000269|PubMed:14687547, ECO:0000269|PubMed:15315762, ECO:0000269|PubMed:24863049, ECO:0000269|PubMed:29622726, ECO:0000269|PubMed:31657721, ECO:0000269|PubMed:7736596, ECO:0000269|PubMed:7916661}.
uniprot
proteins
mass_dalton
47773
uniprot
proteins
mutagenesis
MUTAGEN 25; /note="C->S: Abolished palmitoylation by HHAT. Impaired association with GAS1. Strongly reduces effects of in vivo overexpression; impairs multimer formation; does not affect subcellular location to lipid rafts. Homozygous mice are characterized by a smaller size and holoprosencephaly at 10.5 dpc, and shortening of limbs at 13.5 dpc. They die soon after birth."; /evidence="ECO:0000269|PubMed:11486055, ECO:0000269|PubMed:15075292, ECO:0000269|PubMed:23112049, ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:33038332"; MUTAGEN 26; /note="G->A,S: Does not affect palmitoylation by HHAT."; /evidence="ECO:0000269|PubMed:23112049"; MUTAGEN 26; /note="G->K: Abolished palmitoylation by HHAT."; /evidence="ECO:0000269|PubMed:23112049"; MUTAGEN 27; /note="P->A: Does not affect palmitoylation by HHAT."; /evidence="ECO:0000269|PubMed:23112049"; MUTAGEN 28; /note="G->A: Does not affect palmitoylation by HHAT."; /evidence="ECO:0000269|PubMed:23112049"; MUTAGEN 29; /note="R->A: Does not affect palmitoylation by HHAT."; /evidence="ECO:0000269|PubMed:23112049"; MUTAGEN 32; /note="G->R: Introduces a cleavage site for a furin-like protease resulting in abnormal protein processing; cleavage at this site removes 11 amino acids from the N-terminal domain and reduces affinity of Shh for Ptch1 and signaling potency in assays using chicken embryo neural plate explants and mouse C3H10T1/2 stem cells."; /evidence="ECO:0000269|PubMed:16282375"; MUTAGEN 89; /note="D->V: Moderately reduces Ptch1 binding in vitro and signaling potency in chicken embryo neural plate explant assays compared with wild-type sequence."; /evidence="ECO:0000269|PubMed:16282375"; MUTAGEN 101; /note="Q->H: Does not affect signaling activity in any of Shh signaling assays and causes no apparent defects in cholesterol-mediated autoprocessing reactions."; /evidence="ECO:0000269|PubMed:16282375"; MUTAGEN 116; /note="N->K: Shows no change in activities at different temperatures."; /evidence="ECO:0000269|PubMed:16282375"; MUTAGEN 118; /note="W->G: Causes a failure of Shh processing leading to retention of the immature glycosylated protein within the endoplasmic reticulum of transfected cells; causes a temperature-dependent conformational change that allows Shh to bind Ptch1 at 4 or 32 degrees Celsius but not at 37 degrees Celsius; drastically reduces signaling potency in chicken embryo neural plate explant assays."; /evidence="ECO:0000269|PubMed:16282375"; MUTAGEN 118; /note="W->R: Causes a failure of Shh processing leading to retention of the immature glycosylated protein within the endoplasmic reticulum of transfected cells; causes a temperature-dependent conformational change that allows Shh to bind Ptch1 at 4 or 32 degrees Celsius but not at 37 degrees Celsius; drastically reduces signaling potency in chicken embryo neural plate explant assays."; /evidence="ECO:0000269|PubMed:16282375"; MUTAGEN 189; /note="E->Q: Does not affect signaling activity in any of Shh signaling assays and causes no apparent defects in cholesterol-mediated autoprocessing reactions."; /evidence="ECO:0000269|PubMed:16282375
uniprot
proteins
post_translational_modification
PTM: [Sonic hedgehog protein]: The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity (PubMed:7736596, PubMed:7891723, PubMed:8824192). 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) (PubMed:7736596, PubMed:7891723, PubMed:8824192). Cholesterylation is required for the sonic hedgehog protein N-product targeting to lipid rafts and multimerization (PubMed:24522195, PubMed:8824192). ShhN is the active species in both local and long-range signaling, whereas the C-product (ShhC) is degraded in the endoplasmic reticulum (PubMed:21357747). {ECO:0000269|PubMed:21357747, ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:7736596, ECO:0000269|PubMed:7891723, ECO:0000269|PubMed:8824192}.; PTM: [Sonic hedgehog protein N-product]: Dually lipidated: a cholesterol moiety is attached to its C-terminus following cleavage (PubMed:11389830, PubMed:8824192). N-palmitoylated by HHAT following cholesterylation; palmitoylation is required for sonic hedgehog protein N-product multimerization and full activity (PubMed:11486055, PubMed:15075292, PubMed:23112049). It is a prerequisite for the membrane-proximal positioning (PubMed:24522195). The lipidated N- and C-terminal peptides of ShhN can be cleaved (shedding) (PubMed:24522195). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (PubMed:24522195). The cleavage reduces the interactions with heparan sulfate and is enhanced by SCUBE2 (PubMed:23118222, PubMed:24522195). {ECO:0000269|PubMed:11389830, ECO:0000269|PubMed:11486055, ECO:0000269|PubMed:15075292, ECO:0000269|PubMed:23112049, ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:8824192}.
uniprot
proteins
protein_family
Hedgehog family
uniprot
proteins
pubmed
11389830
uniprot
proteins
pubmed
11430830
uniprot
proteins
pubmed
11486055
uniprot
proteins
pubmed
12679031
uniprot
proteins
pubmed
14687547
uniprot
proteins
pubmed
15075292
uniprot
proteins
pubmed
15315762
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16282375
uniprot
proteins
pubmed
18081866
uniprot
proteins
pubmed
18477453
uniprot
proteins
pubmed
18794898
uniprot
proteins
pubmed
19561611
uniprot
proteins
pubmed
20519495
uniprot
proteins
pubmed
21357747
uniprot
proteins
pubmed
22677548
uniprot
proteins
pubmed
22902404
uniprot
proteins
pubmed
23112049
uniprot
proteins
pubmed
23118222
uniprot
proteins
pubmed
24522195
uniprot
proteins
pubmed
24863049
uniprot
proteins
pubmed
29622726
uniprot
proteins
pubmed
31657721
uniprot
proteins
pubmed
33038332
uniprot
proteins
pubmed
7477329
uniprot
proteins
pubmed
7720571
uniprot
proteins
pubmed
7736596
uniprot
proteins
pubmed
7891723
uniprot
proteins
pubmed
7916661
uniprot
proteins
pubmed
8824192
uniprot
proteins
sequence_length
437
uniprot
proteins
subcellular_location
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 N-product]: Secreted {ECO:0000269|PubMed:33038332, ECO:0000269|PubMed:7891723}. Cell membrane {ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:7891723}; Lipid-anchor {ECO:0000269|PubMed:7891723}. Note=The dual-lipidated sonic hedgehog protein N-product (ShhN) is firmly tethered to the cell membrane where it forms multimers (PubMed:24522195, PubMed:33038332). Further solubilization from the cell surface is achieved by SCUBE2 carrier, which promotes its release from producing cells, allowing it to act as a morphogen for distant signaling (PubMed:22677548, PubMed:24522195, PubMed:33038332). ShhN is then transferred to the CDON-BOC heterodimer and GAS1 coreceptors to reach the patched receptor (PTCH1 or PTCH2) (PubMed:33038332). {ECO:0000269|PubMed:22677548, ECO:0000269|PubMed:24522195, ECO:0000269|PubMed:33038332}.
uniprot
proteins