Sequence conservation in the chagasin family suggests a common trend in cysteine proteinase binding by unrelated protein inhibitors.
The recently described inhibitor of cysteine proteinases from Trypanosoma cruzi, chagasin, was found to have close homologs in several eukaryotes, bacteria and archaea, the first protein inhibitors of cysteine proteases in prokaryotes. These previously uncharacterized 110-130 residue-long proteins share a well-conserved sequence motif that corresponds to two adjacent beta-strands and the short loop connecting them. Chagasin-like proteins also have other conserved, mostly aromatic, residues, and share the same predicted secondary structure. These proteins adopt an all-beta fold with eight predicted beta-strands of the immunoglobulin type. The phylogenetic distribution of the chagasins generally correlates with the presence of papain-like cysteine proteases. Previous studies have uncovered similar trends in cysteine proteinase binding by two unrelated inhibitors, stefin and p41, that belong to the cystatin and thyroglobulin families, respectively. A hypothetical model of chagasin-cruzipain interaction suggests that chagasin may dock to the cruzipain active site in a similar manner with the conserved NPTTG motif of chagasin forming a loop that is similar to the wedge structures formed at the active sites of papain and cathepsin L by stefin and p41.
Rigden
Daniel J
DJ
National Centre of Genetic Resources and Biotechnology, Cenargen/Embrapa, S.A.I.N. Parque Rural, Final W5 Norte, 70770-900 Brasília, Brazil. daniel@cenargen.embrapa.br
Mosolov
Vladimir V
VV
Galperin
Michael Y
MY
D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D030562:Databases, Protein; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; C435145:chagasin, Trypanosoma; D003546:Cysteine Endopeptidases