Hedgehog/Intein domain, found in Hedgehog proteins as well as proteins which contain inteins and undergo protein splicing (e.g. DnaB, RIR1-2, GyrA and Pol). In protein splicing an intervening polypeptide sequence - the intein - is excised from a protein, and the flanking polypeptide sequences - the exteins - are joined by a peptide bond. In addition to the autocatalytic splicing domain, many inteins contain an inserted endonuclease domain, which plays a role in spreading inteins. Hedgehog proteins are a major class of intercellular signaling molecules, which control inductive interactions during animal development. The mature signaling forms of hedgehog proteins are the N-terminal fragments, which are covalently linked to cholesterol at their C-termini. This modification is the result of an autoprocessing step catalyzed by the C-terminal fragments, which are aligned here.
Comment:Step1 of protein splicing is an N-O or N-S shift that leads to an ester or thioester intermediate. As a result, the N-extein binds to the oxygen of a serine or the sulfur of a cysteine sidechain at the amino-terminal splice junction.
Comment:Step 2 of protein splicing is a transesterification in which a nucleophilic residue at the carboxy-terminal splice site attacks the ester/thioester formed in step 1. The result is a branched protein intermediate.
Comment:Step 3 of protein splicing is an asparagine cyclization at the C-terminal end of the intein, which causes excision of the intein and results in splicing of the two exteins by an ester bond.
Comment:Step 4 of protein splicing is a spontaneous rearrangement in the spliced exteins, which results in formation of a peptide bond.
Jiyao W et al.(2023). "The conserved domain database in 2023.",