Dissertaties - Rijksuniversiteit Groningen
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Protein secretion and disulfide bond handling in Bacillus subtilis

(2009) Kouwen, Roelof Hendrik Matthijs

The bacterium Bacillus subtilis serves as an important model organism for research into protein export (secretion) mechanisms in Gram-positive bacteria, and it is widely applied in industry as a “cell factory” for the production of high-value proteins. Over the past years, considerable knowledge has been gained on the protein secretion routes of B. subtilis, and many useful protocols and techniques for protein production and export have been developed. Nevertheless, there are still many proteins that remain difficult to produce in B. subtilis, especially proteins from other organisms, like humans, that contain multiple disulfide bonds. This sets major limits to a full exploitation of B. subtilis for the production of biopharmaceuticals.
This thesis describes research into the mechanisms of protein secretion by B. subtilis, with a strong focus on the secretion of proteins containing disulfide bonds. The mechanisms of disulfide bond formation and breakage have been studied, and differences with other bacteria, such as the important pathogen Staphylococcus aureus have been explored. Furthermore, the efficiency in export and folding of both native and foreign proteins containing disulfide bonds in B. subtilis have been studied. This has resulted in the development of novel strategies for improved production of these proteins and new knowledge about the mode-of-action of a bacterial toxin, the bacteriocin sublancin 168. In addition, several so far unattended aspects of protein secretion in B. subtilis have been studied, such as the overflow of proteins from the major secretion pathway into a special-purpose secretion pathway, and the possible export of proteins via as yet unknown routes. Taken together, the research described here has resulted in new fundamental and applicable insights in the mechanisms of protein secretion in B. subtilis.

file:Title and contents
file:Chapter 1
file:Chapter 2
file:Chapter 3
file:Chapter 4
file:Chapter 5
file:Chapter 6
file:Chapter 7
file:Chapter 8
file:Chapter 9
file:Summary and general discussion
file:Reference list
file:Nederlandse samenvatting voor de leek (Summary in Dutch)
file:List of publications
file:Complete thesis

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