Dokument: Photochemie, Photophysik und Anwendung von light, oxygen, voltage (LOV) Domänen

Titel:

Photochemie, Photophysik und Anwendung von light, oxygen, voltage (LOV) Domänen

Weiterer Titel:

Photochemistry, Photophysics and Application of light, oxygen, voltage (LOV) Domains

URL für Lesezeichen:

https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65916

URN (NBN):

urn:nbn:de:hbz:061-20240603-135902-4

Kollektion:

Dissertationen

Sprache:

Deutsch

Dokumententyp:

Wissenschaftliche Abschlussarbeiten » Dissertation

Medientyp:

Text

Autor:

Hemmer, Stefanie [Autor]

Dateien:

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Dateien vom 23.05.2024 / geändert 23.05.2024

Beitragende:

Krauss, Ulrich [Betreuer/Doktorvater]
Prof. Dr. Jaeger, Karl-Erich [Gutachter]
PD Dr. Pohl, Martina [Gutachter]

Stichwörter:

LOV-Domänen, LOV-Photorezeptoren, Dunkelrückkehr, Dunkelzustand, Lichtzustand, LOV-basierte optogenetische Werkzeuge, maschineller Lernansatz (ML), transiente Absorptionsspektroskopie, reaktiver Triplettzustand, Blauverschiebung, Rotverschiebung, QENS, strukturelle und dynamische Veränderungen, Signalweiterleitung, Entkopplung des Adduktzustandszerfalls, strukturelles Zwischenprodukt, AsLOV2, DsLOV, iLOV, PpSB1-LOV

Dewey Dezimal-Klassifikation:

500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie

Beschreibungen:

Light, Oxygen, Voltage (LOV)-Photorezeptoren sind wichtige Blaulicht-Photorezeptoren, die bei Pflanzen, Pilzen, Bakterien und Protisten vorkommen und eine Anpassung an Lichtveränderungen ermöglichen. Sie durchlaufen einen reversiblen Photozyklus, der ihre Signalfunktion bestimmt. Im Dunkelzustand bindet ein Flavinmononukleotid-Chromophor nicht-kovalent an die LOV-Domäne(n) des Proteins. Belichtung mit blauem Licht führt zu einer Reihe von photochemischen und photophysikalischen Prozessen, welche zur Bildung eines kovalenten Flavin-Cysteinylthiol-Addukts führen. Die Ausbildung dieses Lichtzustands führt zu strukturellen Veränderungen in der LOV-Domäne, die die Aktivität des Photorezeptors kontrollieren und eine physiologische Reaktion auslösen. Im Dunkeln kehrt das LOV-Protein in seinen Dunkelzustand zurück (Dunkelrückkehr), wobei die Flavin-Cystein-Bindung thermisch gebrochen wird, was je nach Protein Sekunden, bis hin zu Tagen dauern kann. Neben ihrer regulatorischen Funktion werden LOV-Photorezeptoren und isolierte LOV-Domänen weitreichend für die Entwicklung von optogenetischen und biophotonischen Werkzeugen eingesetzt. Optogenetische Werkzeuge ermöglichen die reversible Kontrolle biologischer Prozesse mit hoher Präzision, während LOV-basierte biophotonische Werkzeuge als fluoreszierende Proteine zur Visualisierung biologischer Prozesse oder als Photosensibilisatoren zur irreversiblen Ausschaltung von Zellfunktionen genutzt werden. Ein detailliertes Verständnis der Struktur und Mechanismen von LOV-Photorezeptoren ist entscheidend für das Design und die Optimierung solcher Werkzeuge. Die vorliegende Arbeit konzentrierte sich daher auf drei Hauptthemen, die das Verständnis und die Optimierung von LOV-Photorezeptoren und LOV-basierten fluoreszierenden Proteinen betreffen.
Im ersten Teilprojekt wurde der LOV-Photozyklus und die Dunkelrückkehr untersucht, wobei mithilfe eines maschinellen Lernansatzes (ML) versucht wurde, Varianten der Avena sativa Phototropin-1 LOV2 (AsLOV2)-Domäne mit schnellerer und langsamerer Dunkelrückkehr zu erhalten. Über drei Vorhersage-Validierungszyklen wurden eine signifikant schnellere (AsLOV2-I427T/L446M/E475T, τrec = 0,4 ± 0 s) und signifikant langsamere Variante (AsLOV2-N414L/V416L, τrec >103.020 s) erzeugt. Anschließend wurde eine der schnellen Varianten, AsLOV2-V416T, die im Rahmen des ersten Teilprojekts identifiziert wurde, und DsLOV-M49S, eine Variante des LOV-Photorezeptors DsLOV aus Dinoroseobacter shibae, welche ebenfalls eine schnelle Dunkelrückkehr besitzt, mittels transienter Absorptionsspektroskopie untersucht, um die Bildung des reaktiven Triplett-Zustands und die Mechanismen der Adduktbildung zu verstehen. Interessanterweise wurde eine Korrelation zwischen langsamer Adduktbildung und schneller Dunkelrückkehr beobachtet, was auf sterische Wechselwirkungen hindeutet, die den Lichtzustand in LOV-Photorezeptoren stabilisieren. Eine vorläufige Datenanalyse deutet auf das Vorhandensein eines Zwischenprodukts hin, das der Adduktbildung vorausgeht.
Das zweite Teilprojekt befasste sich mit der Anpassung der spektralen Eigenschaften des LOV-basierten, Flavin-bindenden fluoreszierenden Proteins iLOV, das ursprünglich durch gene-shuffling der Gene mehrerer pflanzlicher LOV-Domänen erzeugt wurde. Mittels kombinatorischer Sättigungsmutagenese von drei Aminosäurepositionen in der Nähe des Flavin-Chromophors und einem Ultra-Hochdurchsatz-Screening mittels Fluoreszenz-aktivierter Zellsortierung (Engl. fluorescence activated cell sorting, FACS) wurden verschiedene iLOV-Varianten mit rot- und blauverschobenen spektralen Eigenschaften identifiziert. Im Vergleich zum ursprünglichen iLOV-Protein und zu Literaturdaten wurden hier zwei Varianten mit einer signifikanten Blauverschiebung der Absorptions- und der Fluoreszenzemissionsmaxima (iLOV-V392A/Q489A und iLOV-Q489A/L490R/D491W/G492K/Stop493) und eine Variante mit einem deutlich rotverschobenen Fluoreszenzemissionsmaximum, aber einem blauverschobenen Absorptionsmaximum (iLOV-V392C/G487S/Q489L) identifiziert.
Nicht zuletzt wurden im dritten Teilprojekt die strukturellen und dynamischen Veränderungen während der Dunkelrückkehr des LOV-Photorezeptor PpSB1-LOV aus Pseudomonas putida KT2440 mit einer Kombination aus UV/Vis-, Kernspinresonanz (Engl. nuclear magnetic resonance, NMR)-Spektroskopie und quasielastischen Neutronenstreuungs (QENS)-Messungen untersucht, was neue Einblicke in die Dynamik und die strukturelle Basis der Signalweiterleitung in PpSB1-LOV lieferte. Interessanterweise wurde eine Entkopplung des Zerfalls des Adduktzustands (gemessen durch UV/Vis und NMR) und der strukturellen Rückkehr in den Dunkelzustand (bestimmt durch NMR) beobachtet, was auf das Vorhandensein eines zuvor nicht beobachteten strukturellen Zwischenprodukts hindeutet. Dynamische QENS-Studien ergaben, dass die Dynamik der Proteinseitenketten auf der Zeitskala von Pikosekunden bis Nanosekunden von der Bildung des Adduktzustands beeinflusst wird und dass die Reversion dieser Änderungen offenbar dem vollständigen Brechen des Addukts vorausgeht. Zusammenfassend weisen die hier präsentierten Daten auf eine bisher unbekannte globale dynamische, strukturelle und kinetische Komplexität in diesem Photorezeptor hin.

Light, oxygen, voltage (LOV)-photoreceptors are vital blue-light photoreceptors found in plants, fungi, bacteria, and protists, enabling physiological adaptation to light changes. These receptors undergo a reversible photocycle, determining their signaling function. In darkness, a flavin mononucleotide chromophore binds non-covalently to the protein. Upon blue-light exposure, a series of photochemical and photophysical steps lead to the formation of a covalent flavin-cysteinylthiol-adduct. This light-state formation triggers significant structural changes, controlling the photoreceptor's activity and initiating a physiological response. In the dark, the flavin-cysteine bond in thermally broken and LOV-protein returns to its initial dark state (dark recovery), which can take between seconds to days, depending on the LOV-protein. Besides their regulatory role, LOV-photoreceptors and their isolated sensory LOV-domains are widely used for optogenetic and biophotonic tool development. Optogenetic tools enable reversible control of biological processes with high precision, while LOV-based biophotonic tools serve as fluorescent proteins for visualizing biological processes or photosensitizers for the irreversible ablation of cellular functions. To design and optimize such tools, a comprehensive understanding of the structural and mechanistic aspects of LOV-photoreceptors is crucial. Therefore, this thesis focused on three subjects concerning the understanding and optimization of LOV-photoreceptors and LOV-based fluorescent proteins.
The first subproject investigated the LOV-photocycle and dark recovery kinetics using a machine learning (ML) approach to predict variants of the Avena sativa phototropin-1 LOV2 domain (AsLOV2) with faster and slower dark recovery. Over three prediction-validation cycles a significantly faster (AsLOV2-I427T/L446M/E475T, τrec = 0.4 ± 0 sec) and a significantly slower variant (AsLOV2-N414L/V416L, τrec >103,020 sec) were generated. Subsequently, a fast reverting variant AsLOV2-V416T, identified as part of the first subproject, and DsLOV-M49S, a fast reverting variant of a LOV-photoreceptor of Dinoroseobacter shibae were studied by transient absorption spectroscopy to understand the formation of the reactive triplet state and the mechanisms of adduct formation. Interestingly, a correlation between slow adduct formation and fast adduct reversion was observed, which hint at steric interactions stabilizing the light state in LOV-photoreceptors. Preliminary data analysis suggests the presence of an intermediate preceding adduct formation, whose nature, however, needs to be determined.
The second subproject dealt with the adaptation of the spectral properties of the LOV-based flavin-binding fluorescent protein iLOV, originally generated by shuffling the genes of several plant LOV-domains. Using combinatorial site-saturation mutagenesis of three amino acid positions in the vicinity of the flavin chromophore and an ultra-high throughput screen employing fluorescent activated cell sorting (FACS), different iLOV variants with red- and blue-shifted spectral properties were identified. Compared to the parent iLOV protein and literature data, two variants with a larger blue shift (iLOV-V392A/Q489A and iLOV-Q489A/L490R/D491W/G492K) in both absorption and fluorescence emission and one with larger red shifted fluorescence emission but blue-shifted absorption (iLOV-V392C/G487S/Q489L/Stop493) were identified.
Last but not least, in the third subproject the structural and dynamic changes during the dark recovery in the LOV-photoreceptor PpSB1-LOV of Pseudomonas putida KT2440 was studied using a combination of UV/Vis, nuclear magnetic resonance (NMR)-spectroscopy and quasielastic neutron scattering (QENS)-measurements provided new insights into the structure and dynamics of the LOV-proteins to identify signaling mechanisms. Interestingly, a decoupling of adduct-state decay (measured by UV/Vis and NMR) and structural dark-state recovery (as determined by NMR) was observed, which hinted at the presence of a previously not observed structural intermediate. Dynamic QENS studies revealed that protein side chain dynamics on the picosecond to nanosecond time scale are influenced by adduct state formation and reversion apparently precedes complete adduct rupture. In conclusion, the in this subproject presented data hints at a previously unknown global dynamic, structural and kinetic complexity in this photoreceptor.

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Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Enzymtechnologie

Dokument erstellt am:

03.06.2024

Dateien geändert am:

03.06.2024

Promotionsantrag am:

19.07.2023

Datum der Promotion:

18.03.2024

Heinrich-Heine-Universität Düsseldorf

Dokument: Photochemie, Photophysik und Anwendung von light, oxygen, voltage (LOV) Domänen