Crystal structure of the cysteine protease inhibitor 2 from Entamoeba histolytica: Functional convergence of a common protein fold

Casados‐Vázquez, Luz E.; Lara-González, Samuel; Brieba, Luis G.

doi:10.1016/j.gene.2010.10.006

Cited by 15 publications

(13 citation statements)

References 42 publications

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“…The NPTTG and 2 other motifs of chagasin are essential to form loops 2, 4, and 6, respectively, which are critical for the interactions with the catalytic cysteine of the target proteases (Smith et al 2006;Wang et al 2007;dos Reis et al 2008). Crystal and nuclear magnetic resonance spectroscopy structures of ICPs from T. cruzi, L. mexicana, and E. histolytica suggest that ICPs adopt an immunoglobulin-like fold mainly composed of β-strands and 3 exposed loops (loops 2, 4, and 6), which are directly involved in precise interactions with their target cysteine protease (Smith et al 2006;Ljunggren et al 2007;Figueiredo da Silva et al 2007;Wang et al 2007;Redzynia et al 2008Redzynia et al , 2009Casados-Vázquez et al 2011). The prediction of the secondary and tertiary structures of cryptostatin also demonstrated that cryptostatin consisted of 8 β-strands that progressed in parallel and had an immunoglobulin-fold.…”

Section: Discussionmentioning

confidence: 99%

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Cryptostatin, a chagasin-family cysteine protease inhibitor ofCryptosporidium parvum

Kang

Sohn

et al. 2012

Parasitology

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Cysteine proteases of pathogenic protozoan parasites play pivotal roles in the life cycle of parasites, but strict regulation of their activities is also essential for maintenance of parasite physiology and interaction with hosts. In this study, we identified and characterized cryptostatin, a novel inhibitor of cysteine protease (ICP) of Cryptosporidium parvum. Cryptostatin showed low sequence identity to other chagasin-family ICPs, but 3 motifs (NPTTG, GXGG, and RPW/F motifs), which are evolutionarily conserved in chagasin-family ICPs, were found in the sequence. The overall structure of cryptostatin consisted of 8 β-strands that progressed in parallel and closely resembled the immunoglobulin fold. Recombinant cryptostatin inhibited various cysteine proteases, including papain, human cathepsin B, human cathepsin L, and cryptopain-1, with K i's in the picomolar range. Cryptostatin was active over a wide pH range and was highly stable under physiological conditions. The protein was thermostable and retained its inhibitory activity even after incubation at 95°C. Cryptostatin formed tight complexes with cysteine proteases, so the complexes remained intact in the presence of sodium dodecyl sulfate and β-mercaptoethanol, but they were disassembled by boiling. An immunogold electron microscopy analysis demonstrated diffused localization of cryptostatin within oocystes and meronts, but not within trophozoites, which suggests a possible role for cryptostatin in host cell invasion by C. parvum.

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Section: Discussionmentioning

confidence: 99%

“…(B) Topology diagram of cryptostatin. This diagram represents cryptostatin as a pseudosymmetrical molecule in which 4 β-strands contribute to the formation of each β-sheet(Casados-Vázquez et al 2011)…”

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confidence: 99%

Cryptostatin, a chagasin-family cysteine protease inhibitor ofCryptosporidium parvum

Kang

Sohn

et al. 2012

Parasitology

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“…The predicted type I dockerin domain is very similar to reported crystalline structures (Lytle et al ., ; Pinheiro et al ., ). The middle Chagasin_I42 domain has three conserved loops (DE, BC and FG) able to form a flexible wedge that may block the active site of cysteine protease according to previous studies (Figueiredo da Silva et al ., ; Casados‐Vazquez et al ., ). However, the C‐terminal Chagasin_I42 domain presents a much less compact structure even though conserved amino acids building up these three key loops exist, suggesting that these two Chagasin_I42 domains might have different enzymatic features.…”

Section: Resultsmentioning

confidence: 97%

Dockerin‐containing protease inhibitor protects key cellulosomal cellulases from proteolysis in Clostridium cellulolyticum

et al. 2014

Molecular Microbiology

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SummaryCellulosomes are key for lignocellulosic biomass degradation in cellulolytic Clostridia. Better understanding of the mechanism of cellulosome regulation would allow us to improve lignocellulose hydrolysis. It is hypothesized that cellulosomal protease inhibitors would regulate cellulosome architecture and then lignocellulose hydrolysis. Here, a dockerin-containing protease inhibitor gene (dpi) in Clostridium cellulolyticum H10 was characterized by mutagenesis and physiological analyses. The dpi mutant had a decreased cell yield on glucose, cellulose and xylan, lower cellulose utilization efficiency, and a 70% and 52% decrease of the key cellulosomal components, Cel48F and Cel9E respectively. The decreased cellulolysis is caused by the proteolysis of major cellulosomal components, such as Cel48F and Cel9E. Disruption of cel9E severely impaired cell growth on cellulose while loss of cel48F completely abolished cellulolytic activity. These observations are due to the combinational results of gene inactivation and polar effects caused by intron insertion. Purified recombinant Dpi showed inhibitory activity against cysteine protease. Taken together, Dpi protects key cellulosomal cellulases from proteolysis in H10. This study identified the physiological importance of cellulosome-localized protease inhibitors in Clostridia.

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“…The folds of chagasin and amoebiasin (both members of inhibitor family I42) have also been described as Ig-like 33, 34 . From a Dali pairwise comparison, the structures of IPI and chagasin (PDB code 2NNR) are similar but distant (Z-score 2.2, RMSD 4.2 Å; structural alignment over 110 residues).…”

Section: Resultsmentioning

confidence: 99%

The first structure in a family of peptidase inhibitors reveals an unusual Ig-like fold

Rigden

Chang

et al. 2013

F1000Res

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We report the crystal structure solution of the Intracellular Protease Inhibitor (IPI) protein from Bacillus subtilis, which has been reported to be an inhibitor of the intracellular subtilisin Isp1 from the same organism. The structure of IPI is a variant of the all-beta, immunoglobulin (Ig) fold. It is possible that IPI is important for protein-protein interactions, of which inhibition of Isp1 is one. The intracellular nature of ISP is questioned, because an alternative ATG codon in the ipi gene would produce a protein with an N-terminal extension containing a signal peptide. It is possible that alternative initiation exists, producing either an intracellular inhibitor or a secreted form that may be associated with the cell surface. Homologues of the IPI protein from other species are multi-domain proteins, containing signal peptides and domains also associated with the bacterial cell-surface. The cysteine peptidase inhibitors chagasin and amoebiasin also have Ig-like folds, but their topology differs significantly from that of IPI, and they share no recent common ancestor. A model of IPI docked to Isp1 shows similarities to other subtilisin:inhibitor complexes, particularly where the inhibitor interacts with the peptidase active site.

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Crystal structure of the cysteine protease inhibitor 2 from Entamoeba histolytica: Functional convergence of a common protein fold

Cited by 15 publications

References 42 publications

Cryptostatin, a chagasin-family cysteine protease inhibitor ofCryptosporidium parvum

Cryptostatin, a chagasin-family cysteine protease inhibitor ofCryptosporidium parvum

Dockerin‐containing protease inhibitor protects key cellulosomal cellulases from proteolysis in Clostridium cellulolyticum

The first structure in a family of peptidase inhibitors reveals an unusual Ig-like fold

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