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Dissertation
Structural insights into the allosteric activation mechanism of cGMP-dependent protein kinase I
(2016-05-09)
Cyclic GMP-dependent protein kinase (PKG) is a key transducer in the NO-cGMP signaling pathway. In this line, PKG has been considered an important drug target for treating hypertensive cardiovascular and pulmonary diseases. However, the investigation of PKG’s allosteric activation mechanism has been hampered by a lack of structural information. One of the fundamental questions on the cGMP-dependent activation of PKG is how the enzyme can distinguish cGMP over cAMP and selectively respond to cGMP. To ensure proper ...
Dissertation
Functional characterization of disease-associated mutations in type I cGMP-dependent protein kinase
(2022-08)
Cardiovascular diseases are the leading cause of death worldwide, and while mainly associated with behavioral risk factors, they can also be linked to genetic disorders. The cGMP-dependent protein kinase type I (PKG I) plays a pivotal role in the homeostasis of the vasculature by mediating NO/cGMP-dependent relaxation of vascular smooth muscle cells. A recently described genetic risk factor associated with PKG I results in heritable thoracic aortic aneurysms and dissections (TAAD). Although PKG isoforms Iα and Iβ ...
Dissertation
Mechanistic Insights into the intrinsic Kinase Regulation of LRRK2
(2019-06)
Obwohl Morbus Parkinson (PD) die zweithäufigste neurodegenerative Erkrankung darstellt, ist der Pathomechanismus kaum verstanden. Es ist jedoch erwiesen, dass PD assoziierte Mutationen die Aktivität der Leucine rich repeat kinase 2 (LRRK2) beeinflussen, sodass diese ein potentielles Drug Target darstellt. Für ein besseres Verständnis wurden daher der intrinsische regulatorische Mechanismus und der Einfluss von Mutationen auf LRRK2 untersucht. Zusätzlich wurde der Einfluss von Nanobodies gegen die ROC Domäne von LRRK2 ...
Dissertation
Molekulare Grundlagen der PKA-Lokalisierung durch A-Kinase-Ankerproteine
(2018-08-30)
A-Kinase-Ankerproteine (AKAPs) tragen maßgeblich zur Spezifität des ubiquitären cAMP-Signalweges bei. Dies geschieht unter anderem durch die Verankerung der cAMP-abhängigen Proteinkinase (PKA) an verschiedene Zellorganellen, wodurch die PKA-Effekte lokal und zeitlich begrenzt werden. AKAPs variieren erheblich in Größe und Struktur, zeigen aber als gemeinsames Strukturmotiv eine amphipathische Helix auf. Alle vier Isoformen der regulatorischen Untereinheit der PKA (PKA-R) bilden bei Dimerisierung eine hydrophobe ...
Dissertation
Regulatory mechanisms of Protein kinase A - Isoform mediated fine-tuning
(2023)
cAMP-dependent protein kinase (PKA) is a crucial part in eukaryotic signal transduction and controls biological processes. With a multitude of substrates, a great variety of cellular functions are regulated by PKA. Regulation of metabolism, cell growth and -differentiation, conductivity of ion channels, movement of sperm cells, embryonic development, neuroplasticity as well as conversion of short- to long-term memory are just examples for the many tasks of the kinase. To achieve and coordinate these diverse functions, ...
Dissertation
Pathogenic Mutations in Catalytic Subunit Isoforms of the cAMP-Dependent Protein Kinase
(2023)
Protein kinase A (PKA) is an integral part in a myriad of cellular pathways and a main effector of the second messenger cAMP. Since its discovery in the late 1960s, PKA has become one of the best-studied eukaryotic protein kinases in terms of enzymatic and structural features. Pathological implications of PKA have just started to emerge. There are three main isoforms (α, β, γ) of the catalytic subunit of PKA (PKA-C) which constitute a holoenzyme (R2C2) by association with a regulatory subunit (PKA-R) dimer. While ...
Dissertation
Biochemical Characterization of Microtubule-Associated Serine/Threonine Kinases
(2023)
The association of human microtubule-associated serine/threonine (MAST) kinases with different diseases, such as neurodevelopmental disorders and cancer, leads to hight interest in understanding the function of these understudied kinases. This PhD thesis provides the first consolidated biochemical analysis of three different human MAST kinases (MAST1-3) and the Drosophila melanogaster homologue drop out protein (DOP).