The 26 S proteasome in Entamoeba histolytica: divergence of the substrate binding pockets from host proteasomes

Proteasomes are conserved proteases crucial for proteostasis in eukaryotes and are promising drug targets for protozoan parasites. Yet, the proteasomes of Entamoeba histolytica remain understudied. The study's objective was to analyse the differences in the substrate binding pockets of amoeba p...

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Published in:	BMC research notes Vol. 17; no. 1; pp. 216 - 9
Main Authors:	Joshi, Nidhi, Hosen, S K Yasir, Fahad, Mohd, Narooka, Anil Raj, Gourinath, S, Tiwari, Swati
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 02-08-2024 BioMed Central BMC
Subjects:	26S proteasomes Amino Acid Sequence Amoeba Amoebiasis Analysis Binding Sites Catalytic Domain Comparative analysis Computer applications Conserved sequence Entamoeba histolytica Entamoeba histolytica - enzymology Entamoeba histolytica - metabolism Host-bacteria relationships Humans Leupeptins - pharmacology Mathematical models MG132 Models, Molecular Molecular Docking Simulation Parasites Peptides Physiological aspects Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors - pharmacology Proteasomes Protein Binding Proteins Protozoa Protozoan parasite Protozoan Proteins - chemistry Protozoan Proteins - genetics Protozoan Proteins - metabolism Sequence analysis Substrate preferences Substrate Specificity Therapeutic targets Ubiquitin Ubiquitin-proteasome system Visceral leishmaniasis India Ubiquitin MG132 Entamoeba histolytica Amoebiasis 26S proteasomes Protozoan parasite
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Summary:	Proteasomes are conserved proteases crucial for proteostasis in eukaryotes and are promising drug targets for protozoan parasites. Yet, the proteasomes of Entamoeba histolytica remain understudied. The study's objective was to analyse the differences in the substrate binding pockets of amoeba proteasomes from those of host, and computational modelling of β5 catalytic subunit, with the goal of finding selective inhibitors. Comparative sequence analysis revealed differences in substrate binding sites of E. histolytica proteasomes, especially in the S1 and S3 pockets of the catalytic beta subunits, implying differences in substrate preference and susceptibility to inhibitors from host proteasomes. This was strongly supported by significantly lower sensitivity to MG132 mediated inhibition of amoebic proteasome β5 subunit's chymotryptic activity compared to human proteasomes, also reflected in lower sensitivity of E. histolytica to MG132 for inhibition of proliferation. Computational models of β4 and β5 subunits, and a docked β4-β5 model revealed a binding pocket between β4-β5, similar to that of Leishmania tarentolae. Selective inhibitors for visceral leishmaniasis, LXE408 and compound 8, docked well to this pocket. This functional and sequence-based analysis predicts differences between amoebic and host proteasomes that can be utilized to develop rationally designed, selective inhibitors against E. histolytica.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1756-0500 1756-0500
DOI:	10.1186/s13104-024-06848-y