UniProt functional annotation for Q15465



	UniProt functional annotation for Q15465

UniProt code: Q15465.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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:Q62226}.

Function: [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 (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). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:24863049, ECO:0000303|PubMed:24522195}.

Subunit: Interacts with HHATL/GUP1 which negatively regulates HHAT- mediated palmitoylation of the SHH N-terminus (By similarity). ShhNp is active as a multimer (PubMed:24522195). Interacts with BOC and CDON (By similarity). Interacts with HHIP (PubMed:19561609). Interacts with DISP1 via its cholesterol anchor (PubMed:22902404, PubMed:22677548). Interacts with SCUBE2 (PubMed:24522195, PubMed:22677548). Interacts with glypican GPC3 (By similarity). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:19561609, ECO:0000269|PubMed:22677548, ECO:0000269|PubMed:22902404, ECO:0000269|PubMed:24522195}.

Subcellular location: [Sonic hedgehog protein 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 (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:26875496, PubMed:24522195). {ECO:0000305|PubMed:24522195, ECO:0000305|PubMed:26875496}.

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. {ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:19561609, ECO:0000269|PubMed:20504762}.

Domain: [Sonic hedgehog protein N-product]: 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). {ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195}.

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 (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 reticulum endoplasmic (By similarity). {ECO:0000250|UniProtKB:Q62226, ECO:0000303|PubMed:26875496, ECO:0000305|PubMed:24522195}.

Ptm: [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 (PubMed:24522195). {ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:24522195}.

Ptm: [Sonic hedgehog protein N-product]: 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:24522195, PubMed:23118222). {ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195}.

Mass spectrometry: [Sonic hedgehog protein N-product]: Mass=19.560; Method=Electrospray; Note=Sonic hedgehog protein N-product: soluble product, purified from insect cells.; Evidence={ECO:0000269|PubMed:9593755};

Mass spectrometry: [Sonic hedgehog protein N-product]: Mass=20.167; Method=Electrospray; Note=Sonic hedgehog protein N-product: Membrane- bound product, purified from insect cells.; Evidence={ECO:0000269|PubMed:9593755};

Disease: Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164, ECO:0000269|PubMed:15103725}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=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 expression.

Disease: Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. {ECO:0000269|PubMed:12837695}. Note=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). {ECO:0000269|PubMed:12837695}.

Disease: Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=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. {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}.

Disease: Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). {ECO:0000269|PubMed:24456159}. Note=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. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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:Q62226}.



Function:		[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 (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). {ECO:0000250\|UniProtKB:Q62226, ECO:0000269\|PubMed:10753901, ECO:0000269\|PubMed:24863049, ECO:0000303\|PubMed:24522195}.


Subunit:		Interacts with HHATL/GUP1 which negatively regulates HHAT- mediated palmitoylation of the SHH N-terminus (By similarity). ShhNp is active as a multimer (PubMed:24522195). Interacts with BOC and CDON (By similarity). Interacts with HHIP (PubMed:19561609). Interacts with DISP1 via its cholesterol anchor (PubMed:22902404, PubMed:22677548). Interacts with SCUBE2 (PubMed:24522195, PubMed:22677548). Interacts with glypican GPC3 (By similarity). {ECO:0000250\|UniProtKB:Q62226, ECO:0000269\|PubMed:19561609, ECO:0000269\|PubMed:22677548, ECO:0000269\|PubMed:22902404, ECO:0000269\|PubMed:24522195}.
Subcellular location:		[Sonic hedgehog protein 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 (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:26875496, PubMed:24522195). {ECO:0000305\|PubMed:24522195, ECO:0000305\|PubMed:26875496}.
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. {ECO:0000269\|PubMed:10753901, ECO:0000269\|PubMed:19561609, ECO:0000269\|PubMed:20504762}.
Domain:		[Sonic hedgehog protein N-product]: 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). {ECO:0000269\|PubMed:23118222, ECO:0000269\|PubMed:24522195}.
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 (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 reticulum endoplasmic (By similarity). {ECO:0000250\|UniProtKB:Q62226, ECO:0000303\|PubMed:26875496, ECO:0000305\|PubMed:24522195}.
Ptm:		[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 (PubMed:24522195). {ECO:0000250\|UniProtKB:Q62226, ECO:0000269\|PubMed:24522195}.
Ptm:		[Sonic hedgehog protein N-product]: 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:24522195, PubMed:23118222). {ECO:0000269\|PubMed:23118222, ECO:0000269\|PubMed:24522195}.
Mass spectrometry:		[Sonic hedgehog protein N-product]: Mass=19.560; Method=Electrospray; Note=Sonic hedgehog protein N-product: soluble product, purified from insect cells.; Evidence={ECO:0000269\|PubMed:9593755};
Mass spectrometry:		[Sonic hedgehog protein N-product]: Mass=20.167; Method=Electrospray; Note=Sonic hedgehog protein N-product: Membrane- bound product, purified from insect cells.; Evidence={ECO:0000269\|PubMed:9593755};
Disease:		Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269\|PubMed:12503095}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269\|PubMed:10441331, ECO:0000269\|PubMed:10556296, ECO:0000269\|PubMed:11479728, ECO:0000269\|PubMed:15107988, ECO:0000269\|PubMed:15221788, ECO:0000269\|PubMed:15942952, ECO:0000269\|PubMed:15942953, ECO:0000269\|PubMed:16282375, ECO:0000269\|PubMed:17001669, ECO:0000269\|PubMed:19603532, ECO:0000269\|PubMed:8896572, ECO:0000269\|PubMed:9302262}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269\|PubMed:11471164, ECO:0000269\|PubMed:15103725}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. {ECO:0000269\|PubMed:12837695, ECO:0000269\|PubMed:18417549}. Note=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 expression.
Disease:		Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. {ECO:0000269\|PubMed:12837695}. Note=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). {ECO:0000269\|PubMed:12837695}.
Disease:		Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269\|PubMed:19847792, ECO:0000269\|PubMed:24965254}. Note=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. {ECO:0000303\|PubMed:19847792, ECO:0000303\|PubMed:24965254}.
Disease:		Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). {ECO:0000269\|PubMed:24456159}. Note=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. {ECO:0000305}.