PDBsum entry 1vhh

Signalling protein

PDB id

1vhh

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Contents

			Protein chain

					157 a.a. *

			Ligands

					SO4

			Metals

					_ZN

			Waters ×360

* Residue conservation analysis

PDB id:

1vhh

Links

Name:

Signalling protein

Title:

A potential catalytic site within the amino-terminal signalling domain of sonic hedgehog

Structure:

Sonic hedgehog. Chain: a. Synonym: hhg-1, vhh-1. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: potential. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.70Å

R-factor:

0.191

R-free:

0.261

Authors:

T.M.T.Hall,J.A.Porter,P.A.Beachy,D.J.Leahy

Key ref:

T.M.Hall et al. (1995). A potential catalytic site revealed by the 1.7-A crystal structure of the amino-terminal signalling domain of Sonic hedgehog. Nature, 378, 212-216. PubMed id: 7477329

Date:

03-Oct-95

Release date:

29-Jan-96

PROCHECK

	Headers

	References

Protein chain

Q62226 (SHH_MOUSE) - Sonic hedgehog protein from Mus musculus

Seq: Struc:					437 a.a. 157 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.3.1.-.-

[IntEnz] [ExPASy] [KEGG] [BRENDA]

	Nature 378:212-216 (1995)
PubMed id: 7477329

A potential catalytic site revealed by the 1.7-A crystal structure of the amino-terminal signalling domain of Sonic hedgehog.
T.M.Hall, J.A.Porter, P.A.Beachy, D.J.Leahy.

ABSTRACT

Within the past few years, members of the hedgehog (hh) family of secreted signalling proteins have emerged as the primary signals generated by certain embryonic patterning centres. In vertebrate embryos, for example, sonic hedgehog expression in the notochord appears to be responsible for the local and long-range induction of ventral cell types within the neural tube and somites (reviewed in refs 1, 2). Protein products encoded by hh family members are synthesized as precursors that undergo autoprocessing to generate an amino-terminal domain that appears to be responsible for both local and long-range signalling activities, and a carboxy-terminal domain that contains the autoprocessing activity. As part of an effort to understand how hh family members participate in cell-to-cell signalling, we have determined and report here the crystal structure at 1.7 A of the amino-terminal domain of murine Sonic hedgehog (Shh-N). The structure revealed a tetrahedrally coordinated zinc ion that appears to be structurally analogous to the zinc coordination sites of zinc hydrolases, such as thermolysin and carboxypeptidase A. This previously unsuspected catalytic site represents a distinct activity from the autoprocessing activity that resides in the carboxy-terminal domain.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20024066

B.Z.Stanton, and L.F.Peng (2010).
Small-molecule modulators of the Sonic Hedgehog signaling pathway.

Mol Biosyst, 6, 44-54.

20536384

H.R.Maun, D.Kirchhofer, and R.A.Lazarus (2010).
Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer.

Biol Chem, 391, 881-892.

20024692

S.Guo, J.Zhou, B.Gao, J.Hu, H.Wang, J.Meng, X.Zhao, G.Ma, C.Lin, Y.Xiao, W.Tang, X.Zhu, K.S.Cheah, G.Feng, D.Chan, and L.He (2010).
Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling.

Cell Mol Biol Lett, 15, 153-176.

19561611

B.Bishop, A.R.Aricescu, K.Harlos, C.A.O'Callaghan, E.Y.Jones, and C.Siebold (2009).
Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.

Nat Struct Mol Biol, 16, 698-703.

PDB codes:

2wfq 2wfr 2wft 2wfx 2wg3 2wg4

19274763

C.M.Schreiner, S.M.Bell, and W.J.Scott (2009).
Microarray analysis of murine limb bud ectoderm and mesoderm after exposure to cadmium or acetazolamide.

Birth Defects Res A Clin Mol Teratol, 85, 588-598.

19478089

D.C.Martinelli, and C.M.Fan (2009).
A Sonic Hedgehog Missense Mutation Associated with Holoprosencephaly Causes Defective Binding to GAS1.

J Biol Chem, 284, 19169-19172.

19603532

E.Roessler, K.B.El-Jaick, C.Dubourg, J.I.Vélez, B.D.Solomon, D.E.Pineda-Alvarez, F.Lacbawan, N.Zhou, M.Ouspenskaia, A.Paulussen, H.J.Smeets, U.Hehr, C.Bendavid, S.Bale, S.Odent, V.David, and M.Muenke (2009).
The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.

Hum Mutat, 30, E921-E935.

19561609

I.Bosanac, H.R.Maun, S.J.Scales, X.Wen, A.Lingel, J.F.Bazan, F.J.de Sauvage, S.G.Hymowitz, and R.A.Lazarus (2009).
The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling.

Nat Struct Mol Biol, 16, 691-697.

PDB codes:

3ho3 3ho4 3ho5

19176481

T.Dierker, R.Dreier, A.Petersen, C.Bordych, and K.Grobe (2009).
Heparan Sulfate-modulated, Metalloprotease-mediated Sonic Hedgehog Release from Producing Cells.

J Biol Chem, 284, 8013-8022.

19801637

T.Dierker, R.Dreier, M.Migone, S.Hamer, and K.Grobe (2009).
Heparan sulfate and transglutaminase activity are required for the formation of covalently cross-linked hedgehog oligomers.

J Biol Chem, 284, 32562-32571.

18560152

I.P.Korndörfer, A.Kanitz, J.Danzer, M.Zimmer, M.J.Loessner, and A.Skerra (2008).
Structural analysis of the L-alanoyl-D-glutamate endopeptidase domain of Listeria bacteriophage endolysin Ply500 reveals a new member of the LAS peptidase family.

Acta Crystallogr D Biol Crystallogr, 64, 644-650.

PDB code:

2vo9

18534984

J.A.Buglino, and M.D.Resh (2008).
Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog.

J Biol Chem, 283, 22076-22088.

18794898

J.S.McLellan, X.Zheng, G.Hauk, R.Ghirlando, P.A.Beachy, and D.J.Leahy (2008).
The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla.

Nature, 455, 979-983.

PDB code:

3d1m

18585355

N.Vyas, D.Goswami, A.Manonmani, P.Sharma, H.A.Ranganath, K.VijayRaghavan, L.S.Shashidhara, R.Sowdhamini, and S.Mayor (2008).
Nanoscale organization of hedgehog is essential for long-range signaling.

Cell, 133, 1214-1227.

18498110

S.Ragumani, D.Kumaran, S.K.Burley, and S.Swaminathan (2008).
Crystal structure of a putative lysostaphin peptidase from Vibrio cholerae.

Proteins, 72, 1096-1103.

PDB code:

2gu1

19040769

T.R.Bürglin (2008).
The Hedgehog protein family.

Genome Biol, 9, 241.

17600327

J.E.Ho, E.H.Chung, S.Wall, D.V.Schaffer, and K.E.Healy (2007).
Immobilized sonic hedgehog N-terminal signaling domain enhances differentiation of bone marrow-derived mesenchymal stem cells.

J Biomed Mater Res A, 83, 1200-1208.

17088529

A.Beenken, and M.Mohammadi (2006).
Hedgehogs like it sweet, too.

Proc Natl Acad Sci U S A, 103, 17069-17070.

16615205

E.A.Snell, N.M.Brooke, W.R.Taylor, D.Casane, H.Philippe, and P.W.Holland (2006).
An unusual choanoflagellate protein released by Hedgehog autocatalytic processing.

Proc Biol Sci, 273, 401-407.

17061262

H.W.Ehlen, L.A.Buelens, and A.Vortkamp (2006).
Hedgehog signaling in skeletal development.

Birth Defects Res C Embryo Today, 78, 267-279.

16339763

J.A.Goetz, S.Singh, L.M.Suber, F.J.Kull, and D.J.Robbins (2006).
A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible multimeric form.

J Biol Chem, 281, 4087-4093.

17077139

J.S.McLellan, S.Yao, X.Zheng, B.V.Geisbrecht, R.Ghirlando, P.A.Beachy, and D.J.Leahy (2006).
Structure of a heparin-dependent complex of Hedgehog and Ihog.

Proc Natl Acad Sci U S A, 103, 17208-17213.

PDB codes:

2ibb 2ibg 2ic2

16871364

M.Liu, X.Wang, Z.Cai, Z.Tang, K.Cao, B.Liang, X.Ren, J.Y.Liu, and Q.K.Wang (2006).
A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family.

J Hum Genet, 51, 727-731.

15803137

J.E.Hooper, and M.P.Scott (2005).
Communicating with Hedgehogs.

Nat Rev Mol Cell Biol, 6, 306-317.

15366014

A.L.Egaña, and S.G.Ernst (2004).
Sphedgehog is expressed by pigment cell precursors during early gastrulation in Strongylocentrotus purpuratus.

Dev Dyn, 231, 370-378.

15225411

B.Gao, and L.He (2004).
Answering a century old riddle: brachydactyly type A1.

Cell Res, 14, 179-187.

15289613

B.Y.Hamaoka, C.E.Dann, B.V.Geisbrecht, and D.J.Leahy (2004).
Crystal structure of Caenorhabditis elegans HER-1 and characterization of the interaction between HER-1 and TRA-2A.

Proc Natl Acad Sci U S A, 101, 11673-11678.

PDB code:

1szh

15163793

C.Peters, A.Wolf, M.Wagner, J.Kuhlmann, and H.Waldmann (2004).
The cholesterol membrane anchor of the Hedgehog protein confers stable membrane association to lipid-modified proteins.

Proc Natl Acad Sci U S A, 101, 8531-8536.

15292211

E.Traiffort, C.Dubourg, H.Faure, D.Rognan, S.Odent, M.R.Durou, V.David, and M.Ruat (2004).
Functional characterization of sonic hedgehog mutations associated with holoprosencephaly.

J Biol Chem, 279, 42889-42897.

15044722

M.Bochtler, S.G.Odintsov, M.Marcyjaniak, and I.Sabala (2004).
Similar active sites in lysostaphins and D-Ala-D-Ala metallopeptidases.

Protein Sci, 13, 854-861.

15292190

M.Marcyjaniak, S.G.Odintsov, I.Sabala, and M.Bochtler (2004).
Peptidoglycan amidase MepA is a LAS metallopeptidase.

J Biol Chem, 279, 43982-43989.

PDB codes:

1tzp 1u10

15189162

R.K.Mann, and P.A.Beachy (2004).
Novel lipid modifications of secreted protein signals.

Annu Rev Biochem, 73, 891-923.

12632327

J.Hellemans, P.J.Coucke, A.Giedion, A.De Paepe, P.Kramer, F.Beemer, and G.R.Mortier (2003).
Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips.

Am J Hum Genet, 72, 1040-1046.

12914579

P.E.Jira, H.R.Waterham, R.J.Wanders, J.A.Smeitink, R.C.Sengers, and R.A.Wevers (2003).
Smith-Lemli-Opitz syndrome and the DHCR7 gene.

Ann Hum Genet, 67, 269-280.

11880638

A.L.Simon, E.A.Stone, and A.Sidow (2002).
Inference of functional regions in proteins by quantification of evolutionary constraints.

Proc Natl Acad Sci U S A, 99, 2912-2917.

11835197

R.B.Pepinsky, R.I.Shapiro, S.Wang, A.Chakraborty, A.Gill, D.J.Lepage, D.Wen, P.Rayhorn, G.S.Horan, F.R.Taylor, E.A.Garber, A.Galdes, and T.M.Engber (2002).
Long-acting forms of Sonic hedgehog with improved pharmacokinetic and pharmacodynamic properties are efficacious in a nerve injury model.

J Pharm Sci, 91, 371-387.

11790851

T.Przytycka, R.Srinivasan, and G.D.Rose (2002).
Recursive domains in proteins.

Protein Sci, 11, 409-417.

12372301

Y.Ma, A.Erkner, R.Gong, S.Yao, J.Taipale, K.Basler, and P.A.Beachy (2002).
Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched.

Cell, 111, 63-75.

11455389

B.Gao, J.Guo, C.She, A.Shu, M.Yang, Z.Tan, X.Yang, S.Guo, G.Feng, and L.He (2001).
Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1.

Nat Genet, 28, 386-388.

11284692

F.R.Taylor, D.Wen, E.A.Garber, A.N.Carmillo, D.P.Baker, R.M.Arduini, K.P.Williams, P.H.Weinreb, P.Rayhorn, X.Hronowski, A.Whitty, E.S.Day, A.Boriack-Sjodin, R.I.Shapiro, A.Galdes, and R.B.Pepinsky (2001).
Enhanced potency of human Sonic hedgehog by hydrophobic modification.

Biochemistry, 40, 4359-4371.

11148046

J.E.Jackman, C.R.Raetz, and C.A.Fierke (2001).
Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site.

Biochemistry, 40, 514-523.

10753901

R.B.Pepinsky, P.Rayhorn, E.S.Day, A.Dergay, K.P.Williams, A.Galdes, F.R.Taylor, P.A.Boriack-Sjodin, and E.A.Garber (2000).
Mapping sonic hedgehog-receptor interactions by steric interference.

J Biol Chem, 275, 10995-11001.

PDB code:

3m1n

10555969

E.S.Day, D.Wen, E.A.Garber, J.Hong, L.S.Avedissian, P.Rayhorn, W.Shen, C.Zeng, V.R.Bailey, J.O.Reilly, J.A.Roden, C.B.Moore, K.P.Williams, A.Galdes, A.Whitty, and D.P.Baker (1999).
Zinc-dependent structural stability of human Sonic hedgehog.

Biochemistry, 38, 14868-14880.

10500113

N.Fuse, T.Maiti, B.Wang, J.A.Porter, T.M.Hall, D.J.Leahy, and P.A.Beachy (1999).
Sonic hedgehog protein signals not as a hydrolytic enzyme but as an apparent ligand for patched.

Proc Natl Acad Sci U S A, 96, 10992-10999.

10545376

U.Ryde (1999).
Carboxylate binding modes in zinc proteins: A theoretical study

Biophys J, 77, 2777-2787.

9702193

D.E.Bussiere, S.D.Pratt, L.Katz, J.M.Severin, T.Holzman, and C.H.Park (1998).
The structure of VanX reveals a novel amino-dipeptidase involved in mediating transposon-based vancomycin resistance.

Mol Cell, 2, 75-84.

PDB code:

1r44

10082367

I.L.Alberts, K.Nadassy, and S.J.Wodak (1998).
Analysis of zinc binding sites in protein crystal structures.

Protein Sci, 7, 1700-1716.

9736621

J.Cavarelli, B.Delagoutte, G.Eriani, J.Gangloff, and D.Moras (1998).
L-arginine recognition by yeast arginyl-tRNA synthetase.

EMBO J, 17, 5438-5448.

PDB code:

1bs2

9883719

L.V.Goodrich, and M.P.Scott (1998).
Hedgehog and patched in neural development and disease.

Neuron, 21, 1243-1257.

9593755

R.B.Pepinsky, C.Zeng, D.Wen, P.Rayhorn, D.P.Baker, K.P.Williams, S.A.Bixler, C.M.Ambrose, E.A.Garber, K.Miatkowski, F.R.Taylor, E.A.Wang, and A.Galdes (1998).
Identification of a palmitic acid-modified form of human Sonic hedgehog.

J Biol Chem, 273, 14037-14045.

9846880

R.S.Bhatnagar, K.Fütterer, T.A.Farazi, S.Korolev, C.L.Murray, E.Jackson-Machelski, G.W.Gokel, J.I.Gordon, and G.Waksman (1998).
Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs.

Nat Struct Biol, 5, 1091-1097.

PDB code:

2nmt

9857206

Y.Li, S.Korolev, and G.Waksman (1998).
Crystal structures of open and closed forms of binary and ternary complexes of the large fragment of Thermus aquaticus DNA polymerase I: structural basis for nucleotide incorporation.

EMBO J, 17, 7514-7525.

PDB codes:

2ktq 3ktq 4ktq

9188741

A.V.Efimov (1997).
Structural trees for protein superfamilies.

Proteins, 28, 241-260.

9265630

D.G.McCafferty, I.A.Lessard, and C.T.Walsh (1997).
Mutational analysis of potential zinc-binding residues in the active site of the enterococcal D-Ala-D-Ala dipeptidase VanX.

Biochemistry, 36, 10498-10505.

9302262

E.Roessler, E.Belloni, K.Gaudenz, F.Vargas, S.W.Scherer, L.C.Tsui, and M.Muenke (1997).
Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly.

Hum Mol Genet, 6, 1847-1853.

9009843

M.Hammerschmidt, A.Brook, and A.P.McMahon (1997).
The world according to hedgehog.

Trends Genet, 13, 14-21.

9192620

S.Raghunathan, C.S.Ricard, T.M.Lohman, and G.Waksman (1997).
Crystal structure of the homo-tetrameric DNA binding domain of Escherichia coli single-stranded DNA-binding protein determined by multiwavelength x-ray diffraction on the selenomethionyl protein at 2.9-A resolution.

Proc Natl Acad Sci U S A, 94, 6652-6657.

PDB code:

1kaw

8804825

A.G.Murzin (1996).
Structural classification of proteins: new superfamilies.

Curr Opin Struct Biol, 6, 386-394.

8807822

D.A.Bumcrot, and A.P.McMahon (1996).
Sonic hedgehog: making the gradient.

Chem Biol, 3, 13-16.

8896571

E.Belloni, M.Muenke, E.Roessler, G.Traverso, J.Siegel-Bartelt, A.Frumkin, H.F.Mitchell, H.Donis-Keller, C.Helms, A.V.Hing, H.H.Heng, B.Koop, D.Martindale, J.M.Rommens, L.C.Tsui, and S.W.Scherer (1996).
Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly.

Nat Genet, 14, 353-356.

8896572

E.Roessler, E.Belloni, K.Gaudenz, P.Jay, P.Berta, S.W.Scherer, L.C.Tsui, and M.Muenke (1996).
Mutations in the human Sonic Hedgehog gene cause holoprosencephaly.

Nat Genet, 14, 357-360.

8634241

L.S.Brinen, W.S.Willett, C.S.Craik, and R.J.Fletterick (1996).
X-ray structures of a designed binding site in trypsin show metal-dependent geometry.

Biochemistry, 35, 5999-6009.

PDB codes:

1slu 1slv 1slw 1slx

8752205

N.Perrimon (1996).
Serpentine proteins slither into the wingless and hedgehog fields.

Cell, 86, 513-516.

8917540

R.Zardoya, E.Abouheif, and A.Meyer (1996).
Evolutionary analyses of hedgehog and Hoxd-10 genes in fish species closely related to the zebrafish.

Proc Natl Acad Sci U S A, 93, 13036-13041.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.