trans-Sialidase isolated from trypomastigote forms of IlZypanosoma cruzi, the protozoan parasite that causes Chagas’ disease, is multimeric and heterogeneous in size. We show here that limited proteolysis of trans-sialidase with papain yields a single monomeric polypeptide chain of 70 kDa that conserves full enzymatic activity on soluble and membrane-bound substrates. The papain fragment lacks most otfh e 12-amino acid repeats of the carboxyl-terminal domain that comprises about 50% of the native trans-sialidase. When injected into rabbits, the papain-generated fragmenitn duces antibodies that inhibit trans-sialidase activity and trypomastigote sialylation. The repeats are also not required for the stability of the enzyme or fotrh e correct folding during the biosynthesis in Escherichia coli, but seem essential for trans-sialidase oligomerization. We conclude that transsialidase is composed of two structurally and functionally independent domains.