Family C46

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq

Summary for family C46

NamePeptidase family C46 (hedgehog family)
Family type peptidaseC46.001 - hedgehog protein (Drosophila melanogaster), MEROPS Accession MER0002023 (peptidase unit: 208-421)
Content of familyPeptidase family C46 contains the C-terminal, intein-like domains of the hedgehog proteins, which mediate autolytic cleavage of the proteins.
History Identifier created: MEROPS 3.1 (22 December 1998)
Catalytic typeCysteine
Active site residuesC208 S,T276 H279 
Active siteCys258 (see the Alignment) is directly implicated in the catalytic mechanism (Mann & Beachy, 2000). Asp303, Thr326 and His329 may also contribute (Hall et al., 1997).
Activities and specificitiesThe autolytic cleavage occurs at a conserved -GlyCys- bond, and is mediated by the C-terminal domain of the hedgehog protein. This is the only peptidase activity expressed by the protein. The mechanism of the cleavage has something in common with that of intein proteins. First, an N-S acyl rearrangement of the Gly-Cys peptide bond results in a thioester bond (Mann & Beachy, 2000). Then, the 3-beta hydroxyl group of cholesterol reacts with the thioester, resulting in cleavage and esterification of the new C-terminal Gly of the N-terminal, signaling domain with cholesterol. The side chain of the N-terminal Cys of the C-terminal, catalytic domain may be palmitoylated also. In so far as the peptide bond cleavage is not strictly hydrolysis, the classification of the hedgehog proteins as peptidases could be considered marginal.
Molecular structureThree-dimensional structures have been determined crystallographically for the separated N-terminal and C-terminal domains of hedgehog proteins. The C-terminal domain is the peptidase unit, and has been termed the Hint domain in reference to structural and mechanistic similarities to intein proteins (Hall et al., 1997; Mann & Beachy, 2000); it is included in clan PD because of the structural similarity to inteins.
The N-terminal domain has great similarity to carboxypeptidases in family M15, including the binding of a zinc atom (Hall et al., 1995), but no peptidase activity has been detected, and mutations that would have been expected to eliminate any possible peptidase activity did not eliminate the signalling activities of the domain (Fuse et al., 1999).
ClanPD
SubclanPD(C)
Basis of clan assignmentType family of clan PD.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsHedgehog genes encode precursor proteins that undergo two post-translational cleavage events: removal of the N-terminal signal sequence by signal peptidase, and the autolytic cleavage that separates N-terminal and C-terminal domains. The free N-terminal domains of the hedgehog proteins are responsible for all of the signalling activities, which are important in the development of animals. The esterification of the C-terminal Gly of the signalling domain plays an essential part in this activity (Mann & Beachy, 2000). The receptors are the Patched and perhaps Hedgehog-Interacting Protein gene products.
Statistics for family C46Sequences:1190
Identifiers:15
Identifiers with PDB entries:4
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
hedgehog proteinC46.001Yes
Sonic hedgehog proteinC46.002Yes
Indian hedgehog proteinC46.003Yes
Desert hedgehog proteinC46.004Yes
Tiggy-winkle proteinC46.005-
Warthog protein 1 (Caenorhabditis elegans)C46.006-
Warthog protein 4 (Caenorhabditis sp.)C46.007-
Warthog protein 8 (Caenorhabditis sp.)C46.008-
Warthog protein 1 (Caenorhabditis-type)C46.009-
wrt-7 g.p. (Caenorhabditis elegans)C46.A01-
grd-1 protein (Caenorhabditis elegans)C46.A02-
wrt-6 protein (Caenorhabditis elegans)C46.A04-
qua-1 g.p. (Caenorhabditis elegans)C46.A05-
grd-11 (Caenorhabditis elegans)C46.A06-
grd-2 (Caenorhabditis elegans)C46.A07-
HOG-1 protein (Caenorhabditis elegans )C46.A08-
family C46 non-peptidase homologuesnon-peptidase homologue-
family C46 unassigned peptidasesunassigned-