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Structural and functional characterization of an intramembrane peptidase and a non-peptidase homolog

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  1. Tez No: 403006
  2. Yazar: SİBEL KALYONCU
  3. Danışmanlar: DR. RAQUEL LIEBERMAN
  4. Tez Türü: Doktora
  5. Konular: Biyokimya, Kimya, Kimya Mühendisliği, Biochemistry, Chemistry, Chemical Engineering
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2016
  8. Dil: İngilizce
  9. Üniversite: Georgia Institute of Technology
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: 204

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Özet (Çeviri)

Peptidases play fundamental roles in all living organisms and their dysfunction is associated with a variety of diseases. Although sequences of peptidases encoded in genomes throughout life have become readily available via high throughput sequencing technologies, research on their structural and functional characterizations lags behind due to challenges related to their crystallization and time-intensive biochemical/biophysical studies. Signal Peptide Peptidase (SPP) is an intramembrane aspartyl peptidase that cleaves signal peptides within the hydrophobic region of cellular membrane. SPP plays important roles in cellular functions such as immune system regulation. Structural characterization of membrane proteins including SPP is challenging due to their hydrophobic content which is undesirable in crystallization. Structures of membrane proteins are severely underrepresented: number of unique membrane protein structures is still less than 1% in Protein Data Bank. Here, a new generalizable method was introduced to overcome crystallization challenge of membrane proteins. A toolbox of single chain antibody fragments (scFvs) specific to the EYMPME peptide (EE) epitope was developed for use as co-crystallization chaperones. Structures of designed scFvs were solved and their crystallization propensities were systematically explored to improve their chaperone abilities. Tight complexation of anti-EE scFvs with an EE-tagged archeal SPP and another test membrane protein was demonstrated. Important lessons learned during crystallization and co-crystallization trials of scFvs and SPP are discussed in this dissertation. To understand peptidases at a mechanistic level requires both high resolution structures and extensive structure-function studies in which residues are systematically altered and differences in functionality of the peptidase are measured. Although a low resolution structure of inactive SPP became available during my PhD studies, details on how SPP recognizes and catalyzes its substrate are still not known. Here, preliminary data for a structure-function study to understand substrate gating mechanism of SPP are presented. Finally, structure-function studies of 5-nitroanthralinic acid aminohydrolase (5NAA-A), a metallo-peptidase family member that catalyzes a deamination reaction on a natural, toxic nitroaromatic compound, are presented. 5NAA-A has evolved a function other than peptide hydrolysis but is structurally and evolutionary related to peptidases and is thus classified as a non-peptidase homolog. We characterized 5NAA-A biochemically and biophysically, and obtained snapshots of its mechanism by solving its crystal structures in various states. The 5NAA-A structure and its nucleophilic aromatic substitution mechanism expand our understanding of the great diversity of enzymes capable of transforming natural organic compounds in our ecosystem.

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