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Inhibition of mammalian legumain by some cystatins is due to a novel second reactive site.

Alvarez-Fernandez, Marcia, Barrett, Alan J., Gerhartz, Bernd, Dando, Pam M., Ni, Jian, Abrahamson, Magnus·1999·Journal of Biological Chemistry
DOI 10.1074/jbc.274.27.19195
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Abstract

We have investigated the inhibition of the recently identified family C13 cysteine peptidase, pig legumain, by human cystatin C. The cystatin was seen to inhibit enzyme activity by stoichiometric 1:1 binding in competition with substrate. The Ki value for the interaction was 0.20 nM, i.e. cystatin C had an affinity for legumain similar to that for the papain-like family C1 cysteine peptidase, cathepsin B. However, cystatin C variants with alterations in the N-terminal region and the "second hairpin loop" that rendered the cystatin inactive against cathepsin B, still inhibited legumain with Ki values 0.2-0.3 nM. Complexes between cystatin C and papain inhibited legumain activity against benzoyl-Asn-NHPhNO2 as efficiently as did cystatin C alone. Conversely, cystatin C inhibited papain activity against benzoyl-Arg-NHPhNO2 whether or not the cystatin had been incubated with legumain, strongly indicating that the cystatin inhibited the two enzymes with non-overlapping sites. A ternary complex between legumain, cystatin C, and papain was demonstrated by gel filtration supported by immunoblotting. Screening of a panel of cystatin superfamily members showed that type 1 inhibitors (cystatins A and B) and low Mr kininogen (type 3) did not inhibit pig legumain. Of human type 2 cystatins, cystatin D was non-inhibitory, whereas cystatin E/M and cystatin F displayed strong (Ki 0.0016 nM) and relatively weak (Ki 10 nM) affinity for legumain, respectively. Sequence alignments and molecular…

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Metadata

Authors
Alvarez-Fernandez, M., Barrett, A. J., Gerhartz, B., Dando, P. M., Ni, J., & Abrahamson, M.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1999-07
Volume
274
Issue
27
Pages
19195-19203
ISSN
0021-9258
DOI
10.1074/jbc.274.27.19195
Cited by
238
References
0
Language
en
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