Mechanosensation at the molecular level: A study of a bacterial channel

Duygu Yilmaz

Mechanosensation at the molecular level: A study of a bacterial channel

Vertaalde titel van de bijdrage: Mechanosensatie op moleculair niveau

Duygu Yilmaz

Enzymologie

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Mechanotransductie, de omzetting van fysieke kracht in biochemische informatie, staat aan de basis van de ontwikkeling en fysiologie van organismen. Fysieke krachten regelen een breed scala aan fysiologische processen en de ontregeling van mechanische reacties draagt bij aan belangrijke menselijke ziekten. Uitgebreid onderzoek is uitgevoerd om te ontrafelen hoe mechanische krachten worden omgezet in biochemische signalen en hoe mechanotransductie de functie van de cel beinvloedt. Ondanks alle inspanningen is het moleculaire mechanisme dat ten grondslag ligt aan mechanosensatie nog onbekend.
Op moleculair niveau veroorzaken mechanosensitieve kanalen, celsensoren die de mechanische stimulans in de celmembraan voelen, de mechanosensatie. Ons onderzoek richt zich op een beter begrip van mechanosensatie op moleculair niveau, met behulp van een van de "eenvoudigste" mechanosensors: het “Mechanosensitive channel of Large conductance” (MscL) van de bacterie Escherichia coli. We veranderden MscL en onderzochten het openingsmechanisme door gebruik te maken van verschillende methoden, Ion Mobility Mass Spectrometry (IM-MS), electron paramagnetische resonantie spectroscopie (EPR) en fluorescentiespectroscopie. Met deze methoden hebben we zowel lokale als globale conformationele veranderingen die beginnen in een zeer vroeg stadium van de opening van het kanaal, opgehelderd. Terwijl we meer leerden over het moleculaire mechanisme, pasten we onze bevindingen toe in de ontwikkeling van een tweecomponenten geneesmiddelafgiftesysteem met liposomen. Daarnaast hebben we ook iondoorlaatbare amfifielen die ionkanalen nabootsen, ontworpen.
Kortom, onze resultaten laten een gedetaileerder beeld zien van de opening van MscL. De technieken die we hier hebben ontwikkeld kunnen ook van toepassing zijn om de dynamiek van andere membraaneiwitten te onderzoeken.

Vertaalde titel van de bijdrage	Mechanosensatie op moleculair niveau
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Poolman, Berend, Supervisor Kocer, Armagan, Co-supervisor
Datum van toekenning	8-dec.-2014
Plaats van publicatie	[S.l.]
Uitgever	[S.n.]
Gedrukte ISBN's	978-90-367-7467-3
Elektronische ISBN's	978-90-367-7466-6
Status	Published - 2014

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Title and contents Final publisher's version, 355 KB
Chapter 1Final publisher's version, 391 KB
Chapter 2Final publisher's version, 1,37 MB
Chapter 3Final publisher's version, 1,16 MB
Chapter 4Final publisher's version, 1,81 MB
Chapter 5Final publisher's version, 893 KB
Chapter 6Final publisher's version, 774 KB
Chapter 7Final publisher's version, 494 KB
Complete dissertationFinal publisher's version, 5,83 MB
PropositionsFinal publisher's version, 50,2 KB

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title = "Mechanosensation at the molecular level: A study of a bacterial channel",

abstract = "Mechanotransduction, the conversion of physical force into biochemical information, is fundamental to development and physiology. Physical forces regulate a broad array of physiological processes, and dysregulation of mechanical responses contributes to major human diseases. Extensive research has been done to uncover how mechanical forces are transduced into biochemical signals and how mechanotransduction affects cellular function. Despite all the effort, molecular mechanism underlying mechanosensation is still unknown. At the molecular level, mechanosensation is accomplished by mechanosensitive channels, which are sensors of the cells sensing the mechanical stimulus in the cell membrane. Our research aims at a better understanding of mechanosensation at the molecular level by using one of the “simplest” mechanosensors: Mechanosensitive channel of Large Conductance (MscL) from bacterium Escherichia coli. We engineered MscL and investigated its gating mechanism by employing different methodologies; Ion Mobility Mass Spectrometry (IM-MS), Electron Paramagnetic Resonance Spectroscopy (EPR) and fluorescence spectroscopy. With these methods, we elucidated both global and local conformational changes starting at a very early stage of channel gating. While learning more about its molecular mechanism, we applied our findings to develop two-component drug release system from liposomes. Engineering MscL aside, we also engineered amphiphiles that are permeable to ions, mimicking ion channels. In short, our findings provide insights to a more detailed picture of MscL gating. The techniques we developed here could also be useful in probing the dynamics of other membrane proteins.",

author = "Duygu Yilmaz",

year = "2014",

language = "English",

isbn = "978-90-367-7467-3",

publisher = "[S.n.]",

school = "University of Groningen",

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TY - BOOK

T1 - Mechanosensation at the molecular level

T2 - A study of a bacterial channel

AU - Yilmaz, Duygu

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Y1 - 2014

N2 - Mechanotransduction, the conversion of physical force into biochemical information, is fundamental to development and physiology. Physical forces regulate a broad array of physiological processes, and dysregulation of mechanical responses contributes to major human diseases. Extensive research has been done to uncover how mechanical forces are transduced into biochemical signals and how mechanotransduction affects cellular function. Despite all the effort, molecular mechanism underlying mechanosensation is still unknown. At the molecular level, mechanosensation is accomplished by mechanosensitive channels, which are sensors of the cells sensing the mechanical stimulus in the cell membrane. Our research aims at a better understanding of mechanosensation at the molecular level by using one of the “simplest” mechanosensors: Mechanosensitive channel of Large Conductance (MscL) from bacterium Escherichia coli. We engineered MscL and investigated its gating mechanism by employing different methodologies; Ion Mobility Mass Spectrometry (IM-MS), Electron Paramagnetic Resonance Spectroscopy (EPR) and fluorescence spectroscopy. With these methods, we elucidated both global and local conformational changes starting at a very early stage of channel gating. While learning more about its molecular mechanism, we applied our findings to develop two-component drug release system from liposomes. Engineering MscL aside, we also engineered amphiphiles that are permeable to ions, mimicking ion channels. In short, our findings provide insights to a more detailed picture of MscL gating. The techniques we developed here could also be useful in probing the dynamics of other membrane proteins.

AB - Mechanotransduction, the conversion of physical force into biochemical information, is fundamental to development and physiology. Physical forces regulate a broad array of physiological processes, and dysregulation of mechanical responses contributes to major human diseases. Extensive research has been done to uncover how mechanical forces are transduced into biochemical signals and how mechanotransduction affects cellular function. Despite all the effort, molecular mechanism underlying mechanosensation is still unknown. At the molecular level, mechanosensation is accomplished by mechanosensitive channels, which are sensors of the cells sensing the mechanical stimulus in the cell membrane. Our research aims at a better understanding of mechanosensation at the molecular level by using one of the “simplest” mechanosensors: Mechanosensitive channel of Large Conductance (MscL) from bacterium Escherichia coli. We engineered MscL and investigated its gating mechanism by employing different methodologies; Ion Mobility Mass Spectrometry (IM-MS), Electron Paramagnetic Resonance Spectroscopy (EPR) and fluorescence spectroscopy. With these methods, we elucidated both global and local conformational changes starting at a very early stage of channel gating. While learning more about its molecular mechanism, we applied our findings to develop two-component drug release system from liposomes. Engineering MscL aside, we also engineered amphiphiles that are permeable to ions, mimicking ion channels. In short, our findings provide insights to a more detailed picture of MscL gating. The techniques we developed here could also be useful in probing the dynamics of other membrane proteins.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-7467-3

PB - [S.n.]

CY - [S.l.]

ER -

Mechanosensation at the molecular level: A study of a bacterial channel

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