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Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex
Thesis (MSc)--Stellenbosch University, 2023.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2023
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| _version_ | 1867613818741325824 |
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| access_status_str | Open Access |
| author | Stofberg, Melissa Louise |
| author2 | Zininga, Tawanda |
| author_browse | Stofberg, Melissa Louise Zininga, Tawanda |
| author_facet | Zininga, Tawanda Stofberg, Melissa Louise |
| author_sort | Stofberg, Melissa Louise |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2023. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/129392 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:42:11.774Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/129392 Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex Stofberg, Melissa Louise Zininga, Tawanda Strauss, Erick Stellenbosch University. Faculty of Science. Dept. of Biochemistry. Malaria -- Africa Plasmodium falciparum -- Physiology Protein folding -- Mechanism of action Endoplasmic reticulum Antimalarials Recombinant proteins -- Mechanism of action UCTD Thesis (MSc)--Stellenbosch University, 2023. ENGLISH ABSTRACT: Malaria is a deadly disease, primarily caused by Plasmodium falciparum (P. falciparum) parasites. It affects more than 240 million people annually, with the majority of cases occurring in Africa. Antimalarial drug resistance is rising, and there is a high unmet need for the identification of new drug targets to facilitate the development of novel antimalarial drugs. The protein folding system is an attractive drug target due to its essential role in maintaining the parasite proteome. Some of the members of the endoplasmic reticulum (ER) protein folding system facilitate the folding, secretion, and exportation of parasite proteins to the host cell cytosol. The ER-resident heat shock proteins 90 (Hsp90) and Hsp110, respectively known as PfGrp94 and PfGrp170, have been reported to be essential for parasite survival. These proteins were observed to form a complex in yeast cells, which suggests functional specialization. However, such a relationship has not been established in P. falciparum. This study sought to investigate the structure-functional features of the P. falciparum ER-resident Grp94 and Grp170 proteins, to establish their potential relationship and identify novel small molecule inhibitors. Bioinformatics screening tools (SeeSAR and Schrödinger software) were used to identify promising small molecule inhibitors, which were selective towards PfGrp94 and PfGrp170 over the human Hsp90 and Hsp110 homologs. The recombinant full-length versions of both PfGrp94 and PfGrp170 were successfully produced, and both proteins displayed predominantly α-helical secondary structure features with moderate thermal stability and melting temperatures above 50 °C. The recombinant proteins were observed to directly associate and the association significantly improved resistance to the inhibitor, N-ethyl-carboxamide-adenosine (NECA). Findings from this study provide the first direct evidence for the association of PfGrp94 and PfGrp170 which could be targeted in antimalarial drug development strategies. AFRIKAANSE OPSOMMING: Malaria is 'n dodelike siekte, hoofsaaklik veroorsaak deur Plasmodium falciparum (P. falciparum) parasiete. Dit affekteer meer as 240 miljoen mense jaarliks, met die meerderheid van gevalle wat in Afrika voorkom. Antimalariamiddelweerstand neem toe, en daar is 'n groot onvervulde behoefte vir die identifisering van nuwe geneesmiddelteikens om die ontwikkeling van nuwe antimalariamedisyne te fasiliteer. Die proteïenvouingstelsel is 'n aantreklike geneesmiddelteiken as gevolg van die essensiële rol wat dit speel in die instandhouding van die parasiet proteoom. Sommige lede van die endoplasmiese retikulum (ER) proteïenvouingstelsel fasiliteer die vouing, uitskeiding, en uitvoer van parasietproteïene na die gasheerselsitosol. Die ER-residente hitte-skokproteïene 90 (Hsp90) en Hsp110, onderskeidelik bekend as PfGrp94 en PfGrp170, is aangedui as noodsaaklik vir parasiet oorlewing. Hierdie proteïene vorm ‘n kompleks in gisselle, wat funksionele spesialisering suggereer. So 'n verhouding is egter nie in P. falciparum bevestig nie. Hierdie studie het gepoog om die struktuur-funksionele eienskappe van die P. falciparum ER-residente Grp94 en Grp170 proteïene te ondersoek, om hul potensiële interaksies te bepaal en nuwe klein molekuul-inhibeerders te identifiseer. Met behulp van bio-informatoriese siftingshulpmiddels (SeeSAR en Schrödinger sagteware) was belowende klein molekuul-inhibeerders geïdentifiseer wat selektief is vir PfGrp94 en PfGrp170 teenoor die menslike Hsp90 en Hsp110 homoloë. Die herkombinante volledige weergawes van beide die PfGrp94 en PfGrp170 proteïene was suksesvol vervaardig en het oorwegend α-helikale sekondêre struktuureienskappe getoon met matige termiese stabiliteit en 'n smelttemperatuur bo 50 °C. Daar is waargeneem dat die herkombinante proteïene regstreeks met mekaar assosieer en die assosiasie het beduidende weerstand teen die inhibitor, N-etiel-karboksamied-adenosien (NECA) verbeter. Die bevindinge van hierdie studie verskaf die eerste direkte bewys vir die assosiasie van PfGrp94 en PfGrp170 wat geteiken kan word in antimalariamedikasie-ontwikkelingstrategieë. Masters 2023-11-28T07:54:52Z 2024-02-20T09:57:31Z 2023-11-28T07:54:52Z 2024-02-20T09:57:31Z 2023-12 Thesis https://scholar.sun.ac.za/handle/10019.1/129392 en Stellenbosch University xviii, 148 pages : illustrations (some color_ application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Malaria -- Africa Plasmodium falciparum -- Physiology Protein folding -- Mechanism of action Endoplasmic reticulum Antimalarials Recombinant proteins -- Mechanism of action UCTD Stofberg, Melissa Louise Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex |
| title | Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex |
| title_full | Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex |
| title_fullStr | Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex |
| title_full_unstemmed | Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex |
| title_short | Characterisation of the Plasmodium falciparum ER-localised Hsp90-Hsp110 chaperone complex |
| title_sort | characterisation of the plasmodium falciparum er localised hsp90 hsp110 chaperone complex |
| topic | Malaria -- Africa Plasmodium falciparum -- Physiology Protein folding -- Mechanism of action Endoplasmic reticulum Antimalarials Recombinant proteins -- Mechanism of action UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/129392 |
| work_keys_str_mv | AT stofbergmelissalouise characterisationoftheplasmodiumfalciparumerlocalisedhsp90hsp110chaperonecomplex |