Peptidase C46, hedgehog protein <p>In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:</p><ul> <li>Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.</li><li>Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases. </li></ul><p>In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding. </p><p>Cysteine peptidases have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but commonly also in the two-dimensional structures. These are peptidases in which the nucleophile is the sulphydryl group of a cysteine residue. Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad [<cite idref="PUB00011704"/>]. </p><p>This group of cysteine peptidases correspond to MEROPS peptidase family C46 (clan CH). The type example is the Hedgehog protein from <taxon tax_id="7227">Drosophila melanogaster</taxon> (Fruit fly). </p><p>The hedgehog family of proteins self process by a cysteine-dependent mechanism, which is a one-time autolytic cleavage. It is differentiated from a typical peptidase reaction by the fact that the newly-formed carboxyl groupis esterified with cholesterol, rather than being left free. The three-dimensional structure of the autolytic domain of the hedgehog protein of shows that it is formed from two divergent copies of a D. melanogastermodule that also occurs in inteins, called a 'Hint' domain, <db_xref db="INTERPRO" dbkey="IPR003586"/>, <db_xref db="INTERPRO" dbkey="IPR003587"/> [<cite idref="PUB00000956"/>, <cite idref="PUB00011705"/>].</p><p>The hedgehog protein precursor, HH, is involved in segment polarity and cell to cell communication, and plays important roles in both early embryogenesis and metamorphosis [<cite idref="PUB00001823"/>, <cite idref="PUB00001101"/>, <cite idref="PUB00000880"/>, <cite idref="PUB00001906"/>]. The protein is expressed in embryo stripes [<cite idref="PUB00001823"/>], and in several groups of cells belonging to the foregut, hindgut and various other unidentified tissues. Maximum expression is seen in embryos 6-12 hours after fertilisation, and in pupae 1-24 hours after puparium formation.</p>