Family C12


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

Summary for family C12

NamePeptidase family C12 (ubiquitin C-terminal hydrolase family)
Family type peptidaseC12.001 - ubiquitinyl hydrolase-L1 (Homo sapiens), MEROPS Accession MER0000832 (peptidase unit: 1-223)
Content of familyPeptidase family C12 contains ubiquitinyl hydrolases.
History Identifier created: Biochem.J. 290:205-218 (1993)
Catalytic typeCysteine
Active site residuesQ84 C90 H161 D176 
Active siteThe spacing between Gln84 and Cys90 (numbering as in the alignment) is identical to that in families C1, C2 and C10. The other catalytic residues are His161 and Asp176. The strongest evidence for their identities comes from the tertiary structures (see below).
Activities and specificitiesThe active-site thiol is sensitive to oxidation, and reductants such as dithiothreitol or 2-mercaptoethanol are required for maximal activity. The enzymes are very selective for hydrolysis of bonds formed by the C-terminal Gly of ubiquitin, which may be alpha-peptide, isopeptide, amide or ester bonds. The binding of ubiquitin is primarily electrostatic, being prevented by high salt concentrations, and three conserved acidic residues play major roles: Glu7, Glu11 and Asp30 (Wilkinson et al., 1999). Detailed specificities have been reviewed by Wilkinson (2004).
InhibitorsLike other ubiquitinyl hydrolases (e.g. those in family C19), the peptidases in family C12 are inhibited by ubiquitin aldehyde (Johnston et al., 1999) and ubiquitin vinylsulfone (Hemelaar et al., 2004).
Molecular structureThe tertiary structures of the yeast ubiquitinyl hydrolase YUH1 (C12.002) and human ubiquitinyl hydrolase 1 (C12.003) are very similar, and show many similarities to that of papain. The molecules are bilobed. One lobe consists mainly of helices, and the catalytic Cys is near the start of one of these. The other lobe contains a beta-barrel surrounded by helices, and the catalytic His is at the start of one of the beta-strands. A difference from papain is that the first strand of the beta-barrel precedes the helix bearing the catalytic cysteine in the sequence, whereas in papain the helix precedes all the strands of the barrel.
Basis of clan assignmentProtein fold of the peptidase unit for members of this family and resembles that of papain, the type example for clan CA.
Distribution of family Bacteria details  
Archaea -  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses -  
Biological functionsFamily C12 is one of several families of ubiquitin C-terminal hydrolases. The peptidases of this family are synthesized without propeptides, and remain intracellular. Their biological function is thought to be the removal of ubiquitin from ubiquitinylated proteins and peptides. Ubiquitin is a 76-amino acid protein that is attached to other proteins, commonly as a signal for degradation by the proteasome. Ubiquitin is attached through the carboxyl group of its C-terminal glycine residue either to the N-terminus of another polypeptide or to the epsilon-amino group of a lysine residue, which forms an isopeptide bond. Ubiquitin may also be attached to another molecule of ubiquitin, and proteins targeted for degradation may be polyubiquitinated. In order for ubiquitin to be recycled there is a need for peptidases to liberate ubiquitin by hydrolysis of the C-terminal glycyl bond. Family C12 includes peptidases that can hydrolyze this glycyl bond whether it is an alpha-peptide bond or an isopeptide bond, with various specificities. The actions of these peptidases could have the effect of removing the polypeptide from the ubiquitin-directed trafficking pathway as well as recycling the ubiquitin.
Statistics for family C12Sequences:3104
Identifiers with PDB entries:4
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
ubiquitinyl hydrolase-L1C12.001Yes
ubiquitinyl hydrolase-YUH1C12.002Yes
ubiquitinyl hydrolase-L3C12.003Yes
ubiquitinyl hydrolase-BAP1C12.004-
ubiquitinyl hydrolase-L5C12.005Yes
ubiquitinyl hydrolase isozyme L4 (Mus musculus)C12.007-
ubiquitinyl hydrolase UCH-DC12.008-
Uch2 peptidaseC12.009-
UCHL3 peptidase (apicomplexan)C12.010-
At5g16310 (Arabidopsis thaliana)C12.A01-
At1g65650 (Arabidopsis thaliana)C12.A02-
UCH3 protein (Arabidopsis thaliana)C12.A03-
CG1950 protein (Drosophila melanogaster)C12.A04-
BcDNA.LD24440 (Drosophila melanogaster)C12.A05-
ubh-1 g.p. (Caenorhabditis elegans)C12.A06-
ubh-3 g.p. (Caenorhabditis elegans)C12.A07-
ubh-2 g.p. (Caenorhabditis elegans)C12.A08-
CG8445 protein (Drosophila melanogaster)C12.A09-
uch1 (Schizosaccharomyces pombe-type)C12.A10-
uch1 (Dictyostelium discoideum-type)C12.A11-
UCH54 g.p. (Plasmodium falciparum)C12.A12-
family C12 non-peptidase homologuesnon-peptidase homologue-
family C12 unassigned peptidasesunassigned-