alexa Enzymic activities of two-chain pepsinogen, two-chain pepsin, and the amino-terminal lobe of pepsinogen.
Bioinformatics & Systems Biology

Bioinformatics & Systems Biology

Journal of Proteomics & Bioinformatics

Author(s): Lin XL, Lin YZ, Koelsch G, Gustchina A, Wlodawer A,

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Abstract In order to study the relationships of aspartic proteases, we have modified pepsin, a single-chain eukaryotic enzyme, to a two-chain heterodimer, which resembles aspartic proteases from retrovirus, including human immunodeficiency virus. Two fragments of pepsinogen, residues 1P-172 and 173-326, were expressed separately in Escherichia coli. Mixtures of chains were refolded from urea solutions to generate an active two-chain pepsinogen, which was converted to two-chain pepsin in acid solutions. The intramolecular and bimolecular activation constants (k1 and k2) of two-chain pepsinogen are about 1.5-fold and one-sixth, respectively, of those for pepsinogen. Structural evidence suggests that the faster k1 of two-chain pepsinogen is due to decreased interaction of the propeptide with the pepsin moiety, implying that the rate-limiting step in the intramolecular activation of pepsinogen is the "conformational dissociation" of its propeptide. Two-chain pepsin has the same Km but only one-sixth of the kcat of pepsin. Both pepsinogen chains are capable of independent refolding. The refolding of the NH2-terminal chain, which contains the propeptide and the NH2-terminal lobe, generated a small amount of proteolytic activity which is likely derived from the homodimer of the NH2-terminal lobe. It has been postulated that mammalian aspartic proteases, which contain two structurally homologous lobes, are derived in evolution from a homodimer enzyme by gene duplication and fusion (Tang, J., James, M. N. G., Hsu, I.-N., Jenkins, J. A., and Blundell, T. L. (1978) Nature 271, 618-621). The observation of the homodimer activity of the NH2-terminal lobe of pepsinogen suggests that the interface of the lobes is conservative in evolution.
This article was published in J Biol Chem and referenced in Journal of Proteomics & Bioinformatics

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