A large and accurate collection of peptidase cleavages in the MEROPS database

Rawlings, Neil D.

Exopeptidases cleave near protein termini, and because the binding pockets do not exist are unable to accept any amino acids in some positions. Dipeptidases can only accept residues in the S1 and S1 0 pockets; aminopeptidases are unable to accept any residue in S4-S2, carboxypeptidases in S2 0 -S4 0 , dipeptidyl-peptidases in S4 and S3, tripeptidylpeptidases in S4 and peptidyl-dipeptidases in S3 0 and S4 0 . Some omega peptidases (peptidases which do not cleave normal peptide bonds but release substituted amino acids such as pyroglutamate or cleave isopeptide bonds, such as many deubiquitinating enzymes) may also be unable to accept any residue in certain positions, or it is not possible to interpret cleavages in terms of P4-P4 0 , for example for isopeptidases. There are 36 peptidases with 10 or more cleavages that cannot accept any residue in S4, 35 for S3, 26 for S2, 15 for S2 0 , 22 for S3 0 and 25 for S4 0 . Table 1 shows the number of peptidases showing some selectivity in each binding pocket from S4 to S4 0 for amino acid properties (where 'acidic' is Asp or Glu; 'basic' is Arg, His or Lys; 'aliphatic' is Ile, Leu or Val; 'aromatic' is Phe, Trp or Tyr; and 'small' is Ala, Cys, Gly or Ser). Properties are taken from Livingstone and Barton (32) . Only the categories with the fewest amino acids, and those that do not overlap (with the exception of His, which can also be considered aromatic) have been used. If categories such as 'hydrophobic' and 'polar' are used then nearly every binding pocket is highlighted because each category contains more than half of the amino acids. Most preference is directed towards the S1 (201 different peptidases) and S1 0 (160 different peptidases) pockets. The commonest preferences are for a basic amino acid in the P1 position, small amino acids in P1 and P1 0 , and an aliphatic amino acid in P1 0 . No aromatic amino acids were observed in P4 0 in any of the substrates of these 312 peptidases. For each amino acid category preference was most pronounced in the S1 pocket with the exception of aliphatic amino acids, where most peptidases have a preference in the S1 0 pocket. Preference for acidic amino acids is very rare except in the S1 pocket, and similarly aromatic amino acids are rarely preferred except in S1 and S1 0 .