Investigating the role of loops of the isoaspartyl dipeptidase (IadA) enzyme through protein engineering techniques
Başlık çevirisi mevcut değil.
- Tez No: 797857
- Danışmanlar: DR. MANUEL MÜLLER
- Tez Türü: Yüksek Lisans
- Konular: Genetik, Genetics
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2018
- Dil: İngilizce
- Üniversite: King s College London England
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 33
Özet
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Özet (Çeviri)
Post-translational modifications (PTMS) such as the formation of IsoAspartate (IsoAsp) can result in unconventional residues in the backbone of proteins, thereby resulting in a change in their native structure and hence their function. The IadA enzyme was found to be able to selectively and specifically cleave IsoAsp dipeptides (IsoAsp--Xaa), which are a type of backbone PTM. Protein-engineering techniques such as Site-directed mutagenesis (SDM) can be used to redesign the active site of IadA, creating variants of the IadA enzyme, which ideally would increase the flexibility of the active site, thereby accommodating larger peptides and proteins tha contain IsoAsp residues. In this study, a small library of five mutants was prepared via SDM of the IadA active site. In order to examine the activity of these IadA mutants, activity assays were performed using reversed-phase High Performance Liquid Chromotography (HPLC) technqiues as well as Fluorescence resonance electron transfer (FRET)-based assays. 1 Introduction Since the discovery of IsoAspartate formation in peptides and proteins, there have been several studies based around its significance in the onset of several age-related diseases as well as its biological role in the human body. Extensive research has linked IsoAspartate formation to neurodegeneration that results in Alzheimer's disease.1,2 For example in the study by Morco et al, the hypothesis was put forward that the formation of age-modified forms of amyloidbeta (AB) such as isoD-AB , which is IsoAspartate containing AB, can lead to the formation of or could enhance pathogenic properties of AB and thereby contribute to its aggreagation.1 In addition to this, IsoAspartate formation has also been detected in EF-hand calcium-binding messenger proteins such as Camodulin (CaM) at multiple Asparagine-Glycine and Aspartate-Glycine sites in different Ca-binding domains.3As a result of significant IsoAsp formation at these residues, which are highly conserved Ca-binding sites, it is possible that other EF Ca-binding proteins may also undergo this PTM.3 IsoAsp formation is therefore able to lead to altered biological function as Ca-binding proteins such as Calmodulin, have reduced ability in Ca-dependent enzyme activation.
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