Delineating functionally important regions and residues in the cathepsin B propeptide for inhibitory activity

Chen, Yanmin; Plouffe, Céline; Ménard, Robert; Storer, Andrew C.

doi:10.1016/0014-5793(96)00847-2

Cited by 20 publications

(26 citation statements)

References 20 publications

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“…Although proregion-derived peptides can specifically interact with their cognate enzyme, the K i values are too high to make these peptides efficient inhibitors. Nevertheless these values compare with those found for procathepsin-B-derived peptides (27,36). Crystallographic data have shown that this part of the proregion, which is flexible and fits into the active site of the catalytic domain, contributes weakly to the overall binding energy of interaction between the enzyme and the propeptide (25).…”

Section: Selective Inhibition Of Trypanosomal Versus Mammalian Enzymementioning

confidence: 76%

Inhibition of Trypanosomal Cysteine Proteinases by Their Propeptides

Lalmanach

Lecaille

Chagas

et al. 1998

Journal of Biological Chemistry

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The ability of the prodomains of trypanosomal cysteine proteinases to inhibit their active form was studied using a set of 23 overlapping 15-mer peptides covering the whole prosequence of congopain, the major cysteine proteinase of Trypanosoma congolense. Three consecutive peptides with a common 5-mer sequence YHNGA were competitive inhibitors of congopain. A shorter synthetic peptide consisting of this 5-mer sequence flanked by two Ala residues (AYHNGAA) also inhibited purified congopain. No residue critical for inhibition was identified in this sequence, but a significant improvement in K i value was obtained upon Nterminal elongation. Procongopain-derived peptides did not inhibit lysosomal cathepsins B and L but did inhibit native cruzipain (from Dm28c clone epimastigotes), the major cysteine proteinase of Trypanosoma cruzi, the proregion of which also contains the sequence YHNGA. The positioning of the YHNGA inhibitory sequence within the prosegment of trypanosomal proteinases is similar to that covering the active site in the prosegment of cysteine proteinases, the three-dimensional structure of which has been resolved. This strongly suggests that trypanosomal proteinases, despite their long C-terminal extension, have a prosegment that folds similarly to that in related mammal and plant cysteine proteinases, resulting in reverse binding within the active site. Such reverse binding could also occur for short procongopain-derived inhibitory peptides, based on their resistance to proteolysis and their ability to retain inhibitory activity after prolonged incubation. In contrast, homologous peptides in related cysteine proteinases did not inhibit trypanosomal proteinases and were rapidly cleaved by these enzymes.Cysteine proteinases of the papain superfamily have very similar sequences and a common catalytic mechanism; they are found in bacteria, protozoa, plants, and mammals (1, 2). These enzymes play a critical role in the life cycle of protozoan parasites, in host invasion and alteration of the host immune response (3, 4). Parasite cysteine proteinases from the genus Trypanosoma and Plasmodium, have been reported as putative targets for chemotherapeutic inhibitors (5, 6). The main drawback of this strategy is that cysteine proteinases have a broad substrate specificity, which makes it difficult to develop inhibitors that target individual proteinases.Congopain is a cathepsin L-like cysteine proteinase of Trypanosoma congolense, and cruzipain is the equivalent from Trypanosoma cruzi. These protozoan parasites cause bovine trypanosomiase in Africa and Chagas disease in South America respectively (3, 4). Cruzipain (also called cruzain) is a highly mannosylated glycoprotein and an immunodominant antigen (GP57/51) that is among the best characterized of parasitic cysteine proteinases (7-11). The three-dimensional structure of its recombinant central catalytic domain (215 residues) is very similar to those of papain and cathepsin L (11, 12). Congopain differs only slightly from cruzipain in its enzymatic specifici...

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Section: Selective Inhibition Of Trypanosomal Versus Mammalian Enzymementioning

confidence: 76%

Inhibition of Trypanosomal Cysteine Proteinases by Their Propeptides

Lalmanach

Lecaille

Chagas

et al. 1998

Journal of Biological Chemistry

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“…The interactions within the S sites with concomitant hydrogen bonds to the highly conserved Gly68 are similar in the investigated structures. Although these interactions provide significant binding energy, 37 they do not differ greatly between the two enzymes. The anchoring role of proregion residues that occupy the S2-S3 sites is confirmed also by the structure of the wild type procathepsin L in which the Cys25 is oxidized.…”

Section: Discussionmentioning

confidence: 98%

Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes

et al. 1998

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Synthetic peptides corresponding to the proregions of papain-like cysteine proteases have been shown to be good and selective inhibitors of their parental enzymes. The molecular basis for their selectivity, quite remarkable in some cases, is not fully understood. The recent determination of the crystal structures of three distinct papain-like cysteine protease zymogens allows detailed structural comparisons to be made. The reasons for the specificity shown by each proregion toward its cognate enzyme are explained in terms of the three-dimensional structure of the proregion and the interface between the mature enzyme and the proregion. These comparisons reveal that insertion and substitution of amino acids within the proregion cause major rearrangement of sidechains on the enzyme/proregion interface, allowing detailed surface and charge recognition.

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“…The species distribution of CTLA-2-like proteins has not been explored. Inhibitory regions of the 56-aminoacid rat cathepsin B proregion have also been examined (Chen et al, 1996). Two regions were identified that caused 150-and 625-fold increases in the Ki.…”

Section: Figurementioning

confidence: 99%

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

Dickinson

2002

Critical Reviews in Oral Biology & Medicine

159

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Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily "housekeeping" functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefèvre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.

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Delineating functionally important regions and residues in the cathepsin B propeptide for inhibitory activity

Cited by 20 publications

References 20 publications

Inhibition of Trypanosomal Cysteine Proteinases by Their Propeptides

Inhibition of Trypanosomal Cysteine Proteinases by Their Propeptides

Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

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