A fragment of the major histocompatibility complex class II – associated p41 invariant chain inhibits cruzipain, the major cysteine proteinase from <i>Trypanosoma cruzi</i>

Bevec, Tadeja; Stoka, Veronika; Pungerčič, Galina; Cazzulo, Juán José; Türk, Vito

doi:10.1016/s0014-5793(96)01443-3

Cited by 23 publications

(10 citation statements)

References 23 publications

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“…The wedge-shaped and three-loop arrangement of this fragment bound to the active-site cleft of cathepsin L is reminiscent of the binding of cystatins [74], thus demonstrating the first example of convergent evolution observed in cysteine protease inhibitors, similar to chagasin [262]. Recently, it has been shown that the p41 fragment inhibits human cathepsins V, K, S and F and mouse cathepsin L with K i values in the nM range [263] in addition to human cathepsin L [227] and cruzipain [226]. These findings suggest that the regulation of the proteolytic activity of most of the cysteine cathepsins by the p41 fragment has an important and wideranging control mechanism of antigen presentation [263].…”

Section: Mechanism Of Inhibition Of Cysteine Cathepsinsmentioning

confidence: 84%

“…The discovery that a fragment of the p41 invariant chain (p41Ii) associated with MHC class-II molecules inhibits cathepsin L [194,226,227] suggested the appearance of a new family of protein inhibitors of cysteine cathepsins. This finding was confirmed by the discovery of a new protein, equistatin, isolated from the sea anemone Actinia equina, strongly inhibiting cathepsin L and papain [228] and human cathepsin D [229].…”

Section: Thyropinsmentioning

confidence: 99%

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Cysteine cathepsins: From structure, function and regulation to new frontiers

Türk

Stoka

Vasiljeva

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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1,091

1,054

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It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate "warhead". The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

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Section: Mechanism Of Inhibition Of Cysteine Cathepsinsmentioning

confidence: 84%

Section: Thyropinsmentioning

confidence: 99%

Cysteine cathepsins: From structure, function and regulation to new frontiers

Türk

Stoka

Vasiljeva

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Self Cite

1,091

1,054

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“…Two inhibitors belonging to the recently discovered family of thyropins [88] were shown to be strong inhibitors of cruzipain, with k ass values of 2.4 x 10 7 M -1 s -1 for a fragment of the MHC class II-associated p41 invariable chain [89] and of 6.7 x 10 6 M -1 s -1 for equistatin, from the sea anemone Actinia equina [90].…”

Section: Catalytic Properties: Specificity For Substrates and Inhibitorsmentioning

confidence: 99%

The Major Cysteine Proteinase of Trypanosoma cruzi: A Valid Target for Chemotherapy of Chagas Disease

Cazzulo

Stoka²,

Türk

2001

CPD

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164

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Trypanosoma cruzi, the causative agent of the American Trypanosomiasis, Chagas disease, contains a major cysteine proteinase (CP), cruzipain (also known as cruzain, or GP57/51). The enzyme is a member of the papain C1 family of CPs, with a specificity intermediate between those of cathepsin L and cathepsin B. The enzyme, which is expressed at different levels by different parasite stages, is encoded by a high number of genes (up to 130 in the Tul2 strain), which code for a pre-pro-enzyme. Mature cruzipain consists of a catalytic moiety with high homology to cathepsins S and L, and a C-terminal domain, characteristic of Type I CPs of Trypanosomatids, and absent in all other C1 family CPs described so far. Irreversible inhibitors of cruzipain (peptidyl diazomethylketones, peptidyl fluoromethylketones, peptidyl vinyl sulphones) are able to block the differentiation steps in the parasite's life cycle, and effectively kill the organism. Recently, a vinyl sulphone derivative (N-piperazine-Phe-hPhe-vinyl sulphone phenyl) which is an efficient inhibitor of cruzipain and kills T. cruzi by inducing an accumulation of unprocessed cruzipain in the Golgi cisternae, interfering with the secretory pathway, has been tested in vivo in a mice model (J.H. McKerrow et al.). The curative effects observed, as well as the good bioavailability of the inhibitor and its apparent lack of undesirable side effects, make it a promising lead compound for the development of new drugs for the chemotherapy of Chagas disease.

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“…to parasites such as Leishmania or Trypanosoma cruzi . These organisms require cysteine proteases for survival and invasion [25].…”

Section: Discussionmentioning

confidence: 99%

Thyroglobulin type‐I‐like domains in invariant chain fusion proteins mediate resistance to cathepsin L digestion

et al. 2000

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The MHCII associated invariant chain isoform Ii41 shows homology to a repeat in thyroglobulin (TgR). We show that the Ii31 isoform, which lacks the TgR-like domain, is sensitive to cathepsin L treatment whereas Ii41 displays substantial resistance. The TgR-like sequence of Ii41 was exchanged for thyroglobulin type-IA and -IB repeats, that contain six or four cysteine residues. Resistance to cathepsin L digestion was maintained upon substitution of the Ii41 TgR for homologous sequences from TgR type-IA. Mutation of a conserved cysteine in the TgR domain of an Ii fusion protein strongly reduced resistance to cathepsin L digestion. ß

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A fragment of the major histocompatibility complex class II – associated p41 invariant chain inhibits cruzipain, the major cysteine proteinase from Trypanosoma cruzi

Cited by 23 publications

References 23 publications

Cysteine cathepsins: From structure, function and regulation to new frontiers

Cysteine cathepsins: From structure, function and regulation to new frontiers

The Major Cysteine Proteinase of Trypanosoma cruzi: A Valid Target for Chemotherapy of Chagas Disease

Thyroglobulin type‐I‐like domains in invariant chain fusion proteins mediate resistance to cathepsin L digestion

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