Summary for clan PD
| Clan type peptidase | C46.001 - hedgehog protein (Drosophila melanogaster), MEROPS Accession MER0002023 (peptidase unit: 208-421); PDB accession 1AT0 |
| History | MEROPS 9.4 (31 January 2011) |
| Description | Cysteine nucleophile at the N-terminus of mature enzyme; catalytic residues in the order Cys, Thr, His |
| Contents of clan | This clan contains self-processing proteins |
| Evidence | The tertiary folds of the hedgehog protein (C46.001), the intein associated with V-type proton ATPase catalytic subunit A from Saccharomyces cerevisiae (N09.001) and various inteins from family N10 are similar (Hall et al., 1997). |
| Catalytic mechanism | In the hedgehog protein, processing occurs on the amino side of the nucleophilic Cys. The cysteine attacks the carbonyl carbon atom of the preceding Gly and an N-S acyl rearrangement results in the formation of a thioester bond. Then the 3-beta hydroxyl group of cholesterol reacts with the thioester, resulting in cleavage and esterification of the new C-terminal Gly (Mann & Beachy, 2000).
An intein is a polypeptide insert into another protein (the extein) which is able to release itself from the host protein and splice the two portions of the extein together. Two cleavages occur, on the amino side of a nucleophilic Cys or Ser, and on the carboxyl side of a nucleophilic Asn. The hydroxyl or thiol on the side chain of the first residue of the intein attacks the carbonyl carbon of the preceding amino acid to generate an ester or thiolester intermediate, which is a reaction similar to that in the hedgehog protein. Then transesterification occurs where the first residue of the second portion of the extein attacks the ester or thioester. This results in a branched intermediate where the first portion of the extein is transfered to the side chain of the first residue of the second portion and the peptide bond between the first portion of the extein and the first residue of the intein is broken. The branched intermediate thus has two N-termini. Then the last residue of the intein, which is usually Asn, cyclizes to form a succinimide ring, which results in the breakage of the peptide bond between the Asn and the first residue of the second portion of the extein. The intein is thus released. The ester or thioester bond in the extein then rapidly undergoes an acyl rearrangement to form a normal peptide bond, which is thermodynamically more stable (Raghavan & Minnick, 2009). Neither peptide bond cleavage involves hydrolysis, and hydrolysis, if it occurs, converts the succinimide ring back to Asn. |
| Protein fold | The Hedgehog protein consists of two domains, the N-terminal effector domain and the C-terminal autoprocessing domain. The N-terminal domain has a fold similar to that of zinc D-Ala-D-Ala carboxypeptidases in clan MD, but is not known to have any peptidase activity (Hall et al., 1995). It is the C-terminal domain that are included in clan PD, and each domain consists of two tandem intein-like repeats derived from an ancient duplication event (Hall et al., 1997). Each intein repeat contains six beta strands arranged in an arc, and the active site sits at the junction of the two repeats. Most of the inteins in families N9, N10 and N11 have an endonuclease domain inserted within the intein. |
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Other databases
| SCOP | 51294 |
Families
| C46 |
hedgehog protein (Drosophila melanogaster) |
Yes |
| N09 |
intein-containing V-type proton ATPase catalytic subunit A (Saccharomyces cerevisiae) |
Yes |
| N10 |
intein-containing replicative DNA helicase precursor (Synechocystis sp. PCC 6803) |
Yes |
| N11 |
intein-containing chloroplast ATP-dependent peptide lyase (Chlamydomonas eugametos) |
- |
Distribution of clan PD among Kingdoms of Organisms
