Reviewed, UniProtKB/Swiss-Prot Q62226 (SHH_MOUSE)

Names and origin

Protein names

Recommended name:
    Sonic hedgehog protein
      Short name=SHH
Alternative name(s):
    HHG-1
Cleaved into the following 2 chains:
    1- Recommended name:
            Sonic hedgehog protein N-product
    2- Recommended name:
            Sonic hedgehog protein C-product

Gene names

Name:	Shh
Synonyms:	Hhg1

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	437 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction By similarity.
Subunit structure	Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus. N-product is active as a multimer. Ref.9 Ref.10
Subcellular location	Sonic hedgehog protein C-product: Secreted › extracellular space. Note: The C-terminal peptide diffuses from the cell. Ref.9 Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor. Note: The N-product either remains associated with lipid rafts at the cell surface, or forms freely diffusible active multimers with its hydrophobic lipid-modified N- and C-termini buried inside. Ref.9
Tissue specificity	Expressed in a number of embryonic tissues including the notochord, ventral neural tube, floor plate, lung bud, zone of polarizing activity and posterior distal mesenchyme of limbs. In the adult, expressed in lung and neural retina.
Developmental stage	First detectable during gastrulation.
Induction	By retinoic acid.
Post-translational modification	The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. 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 (N-product). The N-product is the active species in both local and long-range signaling, whereas the C-product has no signaling activity. Cholesterylation is required for N-product targeting to lipid rafts and multimerization. N-palmitoylation of Cys-25 by HHAT is required for N-product multimerization and full activity.
Miscellaneous	Mice overexpressing Shh display digit duplications in both forelimbs and hindlimbs.
Sequence similarities	Belongs to the hedgehog family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Domain	Signal
Molecular function	Developmental protein Hydrolase Protease
PTM	Autocatalytic cleavage Glycoprotein Lipoprotein Palmitate
Technical term	3D-structure
Gene Ontology (GO)
Biological process	Bergmann glial cell differentiation Inferred from direct assay. Source: MGI androgen metabolic process Inferred from mutant phenotype. Source: MGI anterior/posterior pattern formation Inferred from mutant phenotype. Source: MGI axon guidance Inferred from direct assay. Source: MGI blood coagulation Inferred from mutant phenotype. Source: MGI branching involved in lung morphogenesis Inferred from mutant phenotype. Source: MGI branching involved in ureteric bud morphogenesis Inferred from mutant phenotype. Source: MGI camera-type eye development Inferred from direct assay. Source: MGI cell fate specification Inferred from mutant phenotype. Source: MGI determination of left/right symmetry Inferred from mutant phenotype. Source: MGI developmental growth Inferred from mutant phenotype. Source: MGI dorsal/ventral neural tube patterning Inferred from direct assay. Source: MGI embryonic digit morphogenesis Inferred from genetic interaction. Source: MGI embryonic organ development Inferred from mutant phenotype. Source: MGI embryonic skeletal system development Inferred from genetic interaction. Source: MGI formation of anatomical boundary Inferred from mutant phenotype. Source: MGI hair follicle morphogenesis Inferred from mutant phenotype. Source: MGI heart looping Inferred from mutant phenotype. Source: MGI hindbrain development Inferred from mutant phenotype. Source: MGI hindgut morphogenesis Inferred from mutant phenotype. Source: MGI intein-mediated protein splicing Inferred from electronic annotation. Source: InterPro left lung development Inferred from mutant phenotype. Source: MGI male genitalia development Inferred from mutant phenotype. Source: MGI midbrain development Inferred from genetic interaction. Source: MGI myoblast differentiation Inferred from direct assay. Source: MGI negative regulation of T cell proliferation Inferred from mutant phenotype. Source: MGI negative regulation of alpha-beta T cell differentiation Inferred from mutant phenotype. Source: MGI negative regulation of cell migration Inferred from direct assay. Source: MGI negative regulation of proteasomal ubiquitin-dependent protein catabolic process Inferred from mutant phenotype. Source: MGI neural crest cell migration Inferred from mutant phenotype. Source: MGI neuroblast proliferation Inferred from direct assay. Source: MGI neuron fate commitment Inferred from mutant phenotype. Source: MGI odontogenesis of dentine-containing tooth Inferred from mutant phenotype. Source: MGI oligodendrocyte development Inferred from direct assay. Source: MGI osteoblast development Inferred from direct assay. Source: MGI pancreas development Inferred from genetic interaction. Source: MGI patterning of blood vessels Inferred from mutant phenotype. Source: MGI positive regulation of hh target transcription factor activity Inferred from direct assay. Source: MGI positive regulation of mesenchymal cell proliferation Inferred from mutant phenotype. Source: MGI positive regulation of neuroblast proliferation Inferred from direct assay. Source: MGI positive regulation of oligodendrocyte differentiation Inferred from direct assay. Source: MGI positive regulation of protein import into nucleus Inferred from genetic interaction. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: MGI prostate gland development Inferred from mutant phenotype. Source: MGI proteolysis Inferred from electronic annotation. Source: InterPro right lung development Inferred from mutant phenotype. Source: MGI salivary gland morphogenesis Inferred from mutant phenotype. Source: MGI skin development Inferred from mutant phenotype. Source: MGI smoothened signaling pathway involved in regulation of granule cell precursor cell proliferation Inferred from direct assay. Source: MGI spinal cord dorsal/ventral patterning Inferred from mutant phenotype. Source: MGI striated muscle cell differentiation Inferred from direct assay. Source: MGI telencephalon regionalization Inferred from mutant phenotype. Source: MGI trachea development Inferred from mutant phenotype. Source: MGI vasculogenesis Inferred from direct assay. Source: MGI
Cellular component	cell surface Inferred from direct assay. Source: MGI extracellular space Inferred from direct assay. Source: MGI membrane raft Ref.9 Inferred from direct assay. Source: MGI plasma membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	laminin-1 binding Inferred from direct assay. Source: MGI patched binding Inferred from physical interaction. Source: Roslin peptidase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Potential

Chain

25 – 437

413

Sonic hedgehog protein

PRO_0000013211

Chain

25 – 198

174

Sonic hedgehog protein N-product

PRO_0000013212

Chain

199 – 437

239

Sonic hedgehog protein C-product

PRO_0000013213

Regions

Compositional bias

383 – 387

5

Poly-Gly

Sites

Site

198 – 199

2

Cleavage; by autolysis By similarity

Site

244

1

Involved in cholesterol transfer By similarity

Site

268

1

Involved in auto-cleavage By similarity

Site

271

1

Essential for auto-cleavage By similarity

Amino acid modifications

Lipidation

25

1

N-palmitoyl cysteine

Lipidation

198

1

Cholesterol glycine ester

Glycosylation

279

1

N-linked (GlcNAc...) Potential

Experimental info

Mutagenesis

25

1

C → S: 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 E10.5, and shortening of limbs at E13.5. They die soon after birth. Ref.9 Ref.8

Secondary structure

1

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437

Helix Strand Turn

Details...

Beta strand

48 – 52

5

Turn

57 – 60

4

Helix

72 – 76

5

Beta strand

85 – 87

3

Beta strand

92 – 94

3

Helix

95 – 97

3

Helix

101 – 117

17

Beta strand

123 – 127

5

Helix

140 – 143

4

Beta strand

146 – 151

6

Helix

156 – 158

3

Helix

159 – 168

10

Beta strand

172 – 178

7

Beta strand

181 – 185

5

Helix

189 – 192

4

Sequences

	Sequence		Length	Mass (Da)
	Q62226-1 [UniParc]. Last modified June 1, 1998. Version 2. Checksum: D0EB72F08E7860EF	FASTA	437	47,773
	10 20 30 40 50 60 MLLLLARCFL VILASSLLVC PGLACGPGRG FGKRRHPKKL TPLAYKQFIP NVAEKTLGAS 70 80 90 100 110 120 GRYEGKITRN SERFKELTPN YNPDIIFKDE ENTGADRLMT QRCKDKLNAL AISVMNQWPG 130 140 150 160 170 180 VKLRVTEGWD EDGHHSEESL HYEGRAVDIT TSDRDRSKYG MLARLAVEAG FDWVYYESKA 190 200 210 220 230 240 HIHCSVKAEN SVAAKSGGCF PGSATVHLEQ GGTKLVKDLR PGDRVLAADD QGRLLYSDFL 250 260 270 280 290 300 TFLDRDEGAK KVFYVIETLE PRERLLLTAA HLLFVAPHND SGPTPGPSAL FASRVRPGQR 310 320 330 340 350 360 VYVVAERGGD RRLLPAAVHS VTLREEEAGA YAPLTAHGTI LINRVLASCY AVIEEHSWAH 370 380 390 400 410 420 RAFAPFRLAH ALLAALAPAR TDGGGGGSIP AAQSATEARG AEPTAGIHWY SQLLYHIGTW 430 LLDSETMHPL GMAVKSS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity." Echelard Y., Epstein D.J., St Jacques B., Shen L., Mohler J., McMahon J.A., McMahon A.P. Cell 75:1417-1430(1993) [PubMed: 7916661] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: C57BL/6J. Tissue: Embryo.
[2]	McMahon A.P. Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 122.
[3]	"Products, genetic linkage and limb patterning activity of a murine hedgehog gene." Chang D.T., Lopez A., von Kessler D.P., Chiang C., Simandl B.K., Zhao R., Seldin M.F., Fallon J.F., Beachy P.A. Development 120:3339-3353(1994) [PubMed: 7720571] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], AUTOPROTEOLYTIC CLEAVAGE.
[4]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Limb.
[6]	"Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis." Roelink H., Porter J.A., Chiang C., Tanabe Y., Chang D.T., Beachy P.A., Jessell T.M. Cell 81:445-455(1995) [PubMed: 7736596] [Abstract] Cited for: FUNCTION, AUTOPROTEOLYTIC CLEAVAGE.
[7]	"Cholesterol modification of hedgehog signaling proteins in animal development." Porter J.A., Young K.E., Beachy P.A. Science 274:255-259(1996) [PubMed: 8824192] [Abstract] Cited for: CHOLESTERYLATION AT GLY-198.
[8]	"Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal." Chamoun Z., Mann R.K., Nellen D., von Kessler D.P., Bellotto M., Beachy P.A., Basler K. Science 293:2080-2084(2001) [PubMed: 11486055] [Abstract] Cited for: PALMITOYLATION AT CYS-25, MUTAGENESIS OF CYS-25.
[9]	"Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates." Chen M.-H., Li Y.-J., Kawakami T., Xu S.-M., Chuang P.-T. Genes Dev. 18:641-659(2004) [PubMed: 15075292] [Abstract] Cited for: PALMITOYLATION AT CYS-25, MUTAGENESIS OF CYS-25, SUBUNIT, SUBCELLULAR LOCATION.
[10]	"Mammalian Gup1, a homolog of Saccharomyces cerevisiae glycerol uptake/transporter 1, acts as a negative regulator for N-terminal palmitoylation of Sonic hedgehog." Abe Y., Kita Y., Niikura T. FEBS J. 275:318-331(2008) [PubMed: 18081866] [Abstract] Cited for: INTERACTION WITH HHATL.
[11]	"A potential catalytic site revealed by the 1.7-A crystal structure of the amino-terminal signalling domain of Sonic hedgehog." Hall T.M.T., Porter J.A., Beachy P.A., Leahy D.J. Nature 378:212-216(1995) [PubMed: 7477329] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 34-195.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

X76290 mRNA. Translation: CAA53922.1.
AK077688 mRNA. Translation: BAC36956.1.
BC063087 mRNA. Translation: AAH63087.1.

IPI

IPI00123314.

PIR

A49425.

RefSeq

NP_033196.1.

UniGene

Mm.57202

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1VHH	X-ray	1.70	A	34-195	[»]
3D1M	X-ray	1.70	A/B	26-189	[»]

ModBase

Search...

Protein family/group databases

MEROPS

C46.002.

Genome annotation databases

Ensembl

ENSMUSG00000002633. Mus musculus. [Contig view]

GeneID

20423.

KEGG

mmu:20423.

Organism-specific databases

MGI

MGI:98297. Shh.

Phylogenomic databases

HOGENOM

Q62226.

HOVERGEN

Q62226.

OMA

Q62226. LGMAVKS.

Gene expression databases

ArrayExpress

Q62226.

Bgee

Q62226.

CleanEx

MM_SHH.

GermOnline

ENSMUSG00000002633. Mus musculus.

Family and domain databases

InterPro

IPR003586. Hedgehog_hint_C.
IPR003587. Hedgehog_hint_N.
IPR000320. HH_signal.
IPR006141. Intein_splicing_site.
IPR001657. Peptidase_C46.
IPR001767. Peptidase_C46_hint.
[Graphical view]

Pfam

PF01085. HH_signal. 1 hit.
PF01079. Hint. 1 hit.
[Graphical view]

PIRSF

PIRSF009400. Peptidase_C46. 1 hit.

PRINTS

PR00632. SONICHHOG.

SMART

SM00305. HintC. 1 hit.
SM00306. HintN. 1 hit.
[Graphical view]

PROSITE

PS50817. INTEIN_N_TER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

298432.

SOURCE

Search...

Entry information

Entry name

SHH_MOUSE

Accession

Primary (citable) accession number: Q62226

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	June 1, 1998
Last modified:	June 16, 2009
This is version 103 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)