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  • 1.
    Duong, Sun
    Linköping University, Department of Physics, Chemistry and Biology.
    Evaluation of novel fluorescent probes for in vivo Transthyretin amyloid using fibrils generated in vitro under varying conditions2019Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Transthyretin (TTR) amyloidosis is a disease that appears in three variants. One variant affects the elderly population with heart failure, the other two variants are hereditary and caused by an amino acid substitution in the gene, resulting in polyneuropathy and/or heart issues depending on the amino acid substitution. However, in all three variants, other organs may also be affected with amyloid deposition in the disease course. Amyloid fibrils of TTR (ATTR) contains a mixture of full-length protein and fragments (50-127).

    Luminescent conjugated oligothiophenes (LCO’s) are novel amyloid binding probes used to stain amyloid fibrils and these amyloid probes have the feature of characterizing the amyloid structure in terms of fluorescence spectra. Apart from LCO’s, a few other amyloid binding probes are used to stain recombinant amyloid transthyretin and native transthyretin for binding studies. The majority of generated TTR aggregates in vitro did not have the characteristic fluorescence spectra when bound to LCO’s and was observed as a clumped gel-like aggregate. The generation of recombinant TTR fibrils in vitro using the mutant TTR-T49M to obtain an aggregation prone fragment (50-127) after being treated with cyanogen bromide had a low yield of in vivo amyloid-like fibrils, but with characteristic LCO spectra. Carpal tunnel ATTR often precedes ATTR deposition in heart tissue. Amyloid transthyretin in carpal tunnel tissues was stained with LCO’s and used as a reference in the comparison against the in vitro generated recombinant amyloid transthyretin fibrils. This project also includes quantification of amyloid transthyretin in a few selected parts of the carpal tunnel tissue using ImageJ. In the long run this method could help in diagnosing TTR amyloidosis.

  • 2.
    Fornander, Erik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology.
    Smedéus, Lydia
    Linköping University, Department of Physics, Chemistry and Biology.
    Mattsson, Elin
    Linköping University, Department of Physics, Chemistry and Biology.
    Strannermyr, Malin
    Linköping University, Department of Physics, Chemistry and Biology.
    Lassi, Johan
    Linköping University, Department of Physics, Chemistry and Biology.
    Sorjonen, Lovisa
    Linköping University, Department of Physics, Chemistry and Biology.
    Bergqvist, Jonathan
    Linköping University, Department of Physics, Chemistry and Biology.
    Duong, Sun
    Linköping University, Department of Physics, Chemistry and Biology.
    Characterization of Affinity and Stability for the C-lobe of Calmodulin in Plasmodium falciparum.2016Independent thesis Basic level (degree of Bachelor), 10,5 credits / 16 HE creditsStudent thesis
    Abstract [en]

    Protein science gives important tools for designing efficient pharmaceuticals with specific target molecules. Calmodulin (CaM) is an essential protein existing in most species. In humans and the parasite Plasmodium falciparum the sequence differs in a few amino acids. Since the pandemic disease malaria is caused by P.falciparum, differences between human CaM and P.falciparum CaM is of interest for specific inhibition of CaM in P.falciparum.

     

    In this project, differences in affinity and stability for the C-lobe of CaM (CaMC) in both human and P.falciparum was studied as a result of ligand binding and differences in thermal- and chemical stability. Furthermore, the secondary structure was examined by circular dichroism spectroscopy (CD). The stability differences between human CaMC and P.falciparum CaMC was examined by using CD and fluorescence spectroscopy. Fluorescence spectroscopy was also used when examining ligand binding with Trifluoperazine (TFP), 8-Anilinonaphthalene-1-sulfonic acid (ANS) and Artemisinin (ART). Both human CaMC and P.falciparum CaMC contains two tyrosines in their primary structure, which along with ANS was used as fluorophores when practising fluorescence spectroscopy. Human CaMC and P.falciparum CaMC were compared at different levels of structure and ligand docking by modelling.

     

    Modelling with PyMOL and sequence alignment with protein BLAST showed that the structures of CaMC in human and CaMC in P.falciparum are similar, however, the primary structure differs at eleven positions whereof three of them are considered to be significant. Along with these differences in the primary structure there are other structural differences such as conformational openness, the area of the hydrophobic cleft and the structure of the reactive loops. The structural analysis performed by CD consolidates that CaMC have a similar secondary structure in human and P.falciparum. The results from the thermal and chemical stability analysis shows that both P.falciparum CaMC and human CaMC have stable structures. The fluorescence measurements of binding TFP to CaMC implies a higher binding affinity to human CaMC than P.falciparum CaMC. Moreover, further fluorescence measurements indicate a binding of ART to P.falciparum CaMC.

     

    To gain a better understanding of both P.falciparum CaMC and human CaMC it would be of interest to investigate more specific ligands bound to the structures i.e. derivates of TFP and ART with lower Kd than the original TFP and ART; how they affect the stability, the structure and the activity of the C-lobe. This knowledge could be helpful in the development of malaria treatments. 

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