Family M87

Family

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

Summary for family M87

Family type peptidaseM87.001 - chloride channel accessory protein 1 (Homo sapiens), MEROPS Accession MER0203744 (peptidase unit: 22-305)
Content of familyFamily M87 contains self-cleaving proteins.
History Identifier created: MEROPS 9.8 (17 December 2012)
Family M87 is the first family of self-cleaving proteins that do not have serine, threonine or cysteine nucleophiles. Human CLCA1 (chloride channel activated 1, M87.001) cleaves itself into a two-chain form, consisting of a 70 KDa chain derived from the N-terminal portion of the protein and a 38 kDa chain derived from the C-terminal portion (Yurtsever et al., 2012). Self-cleavage is a prerequisite for activation of the chloride channel proteins. The number of homologues in the genome varies with the species, from three in human to seven in mouse (Yurtsever et al., 2012).
Catalytic typeMetallo
Active site residuesH156 E157 H160 
Active siteHuman CLCA1 contains a motif, HEXXHXXXGXXDE, within the N-terminal portion of the protein similar to that found in other metallopeptidases, particularly the Met-zincins from clan MA (where the motif is the slightly smaller HEXXHXXGXXH). Mutagenesis of the His, Glu and Asp residues in this motif has shown that all are essential for cleavage (Bothe et al., 2012; Yurtsever et al., 2012). Comparison with the Met-zincin motif (clan MA) suggests that the two histidines are metal ligands, the first glutamic is a catalytic residue, and the Asp and Glu are second catalytic residue and third metal ligand, though not necessarily in this order..
Activities and specificitiesSelf-cleavage occurs at a well-conserved site, in which P1 is basic or Gly, P1" is small (predominantly Gly or Ala), P2" is hydrophobic, P3" is Tyr and P6" is Gly. Cleavage is intermolecular, and human CLCA1 can cleave a synthetic quenched fluorescent substrate and be cleaved by CLCA2 and CLCA4 (Yurtsever et al., 2012).
InhibitorsThe metal chelators EDTA and 1,10-phenanthroline inhibit self-cleavage (Yurtsever et al., 2012).
Molecular structureMembers of family M87 are either soluble or possess a single transmembrane region in the C-terminal chain and are therefore unlikely to form chloride channels themselves (Bothe et al., 2012; Yurtsever et al., 2012). In CLCA proteins with a transmembrane region, only the processed N-terminal chain is secreted (Bothe et al., 2012). No crystal structure has been determined for any member of the family and family M87 has not been assigned to a clan.
Clanunassigned
Distribution of family Bacteria -  
Archaea -  
Protozoa -  
Fungi -  
Plants -  
Animals details  
Viruses -  
Biological functionsCLCA1 controls calcium-activated chloride channel activation, which in turn controls mucus secretion, especially in the respiratory tract. CLCA1 is a critical mediator of hypersecretory lung diseases such as asthma, cystic fibrosis abd chronic obstructive pulmonary disease (COPD) (Yurtsever et al., 2012). The CLCA proteins are synthesized with a signal peptide but not an N-terminal activation peptide (Yurtsever et al., 2012). The N-terminal chain alone can modulate chloride channels, implying that the C-terminal chain acts as an inhibitor prior to cleavage (Yurtsever et al., 2012). A mutant form of the N-terminal chain of CLCA1 in which the catalytic His was replaced was able to modulate the chloride channel, which implies that proteolytic activity is not required once self-processing has occurred (Yurtsever et al., 2012).
Statistics for family M87Sequences:684
Identifiers:6
Identifiers with PDB entries:0
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
chloride channel accessory protein 1M87.001-
chloride channel accessory protein 4M87.002-
chloride channel accessory protein 2M87.003-
chloride channel accessory protein 7 (Mus musculus)M87.004-
chloride channel accessory protein 4 (Mus musculus)M87.005-
chloride channel accessory protein 1 (Mus musculus)M87.006-
family M87 non-peptidase homologuesnon-peptidase homologue-
family M87 unassigned peptidasesunassigned-