InterPro domain: IPR034193

This domain is found in some members of peptidase family S8 (subtilisins) [ 1 ], such as PCSK9 (proprotein convertase subtilisin/kexin type 9; MEROPS identifier S08.039), proteinase K (S08.054), proteinase T (S08.061) from the fungus Tritirachium album Limber [ 2 ], and other subtilisin-like serine endopeptidases. PCSK9 post-translationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation, and is a target for drugs for hypercholesterolaemia. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR [ 3 ]. Characterized proteinases K are secreted endopeptidases that are not substrate-specific and function in a wide variety of species in different pathways. It can hydrolyze keratin and other proteins with subtilisin-like specificity [ 4 ]. The number of calcium-binding motifs found in these differ [ 5 ].

The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence [ 6 ]. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses [ 7 ]. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [ 8 , 8 ]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [ 8 , 8 ]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [ 8 ].

1. Evolutionary families of peptidases. Biochem. J. 290 ( Pt 1), 205-18
2. Cloning and expression of the gene encoding a novel proteinase from Tritirachium album limber. Adv. Exp. Med. Biol. 379, 95-104
3. A review of PCSK9 inhibition and its effects beyond LDL receptors. J Clin Lipidol 10, 1073-80
4. Proteinase K from Tritirachium album Limber. Eur. J. Biochem. 47, 91-7
5. The effect of calciums on molecular motions of proteinase K. J Mol Model 17, 289-300
6. Subtilases: the superfamily of subtilisin-like serine proteases. Protein Sci. 6, 501-23
7. Families of serine peptidases. Meth. Enzymol. 244, 19-61