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Role of glycosylation of ionotropic glutamate receptors in mammalian neurons
Danačíková, Šárka ; Horák, Martin (advisor) ; Kriška, Ján (referee)
Glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. There are two distinct types of glutamate receptors, ionotropic and metabotropic, present in the mammalian excitatory synapses. My thesis is focused on the ionotropic glutamate receptors, which play critical roles in learning and memory formation. The main subtypes of ionotropic glutamate receptors are α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate receptors. All types of the ionotropic glutamate receptors, which are assembled as tetramers, contain many glycosylation sites, which can be modified by glycans or monosaccharides. The glycans and monosaccharides attached to the ionotropic glutamate receptors have been shown to regulate key processes such as folding of the subunits, transport to the cell surface as well as their functional properties. Recent literature also suggests that many neurological and psychiatric disorders such as schizophrenia exhibit abnormal glycosylation of ionotropic glutamate receptors. Thus, understanding of the molecular mechanisms, which regulate the glycosylation of the ionotropic glutamate receptors, may be important for developing new therapies for the patients with altered functioning of the glutamatergic synapses in the...
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The role of posttranslational modifications in the molecular mechanism of the circadian clock
Janáčová, Klára ; Sumová, Alena (advisor) ; Sládek, Martin (referee)
The timing of the biological processes of organism is controlled by an endogenous circadian clock. The molecular clock is present in almost every cell and is synchronized with the external environment. The main mechanism of the clock is a transcription-translation feedback loop. The 24-hour circadian rhythm period is provided by reversible posttranslational modifications (PTMs) of the clock proteins and another regulators of the circadian clock. PTMs are further important for clock entrainment, their regulation by metabolic state in the cell, and reciprocal regulation of the circadian clock end cell cycle. Phosphorylation, histones PTMs, acetylation, SUMOylation, ubiquitination, O-linked N-acetylglucosamination and polyADP-ribosylation play a crucial role. The molecular mechanism of the biological clock is an evolutionarily conserved mechanism found in most organisms. This bachelor thesis summarizes the knowledge about the role of PTMs in the molecular mechanism of the mammalian and human circadian clocks. Key words: circadian clock, clock genes, clock proteins, posttranslational modifications
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Posttranlational protein modifications in response to DNA damage
Kroupa, Michal ; Hodný, Zdeněk (advisor) ; Novotný, Marian (referee)
- 5 - Abstract Thousands of DNA lessions occur in each cell every day of which the most toxic are double-strand breaks (DSBs). Signaling of their presence and subsequent repair are mediated by so-called DNA-damage response mechanism (DDR), which involves accumulation of many effector proteins into DSBs sites. These molecular accumulation at DSBs are termed DNA damage foci. Depending on presence of sister chromatid, DSBs are repaired by two major mechanisms: by homologous recombination and by non-homologous end joining. Both pathways lead to activation of checkpoint kinases (Chk1 or Chk2) which iniciate checkpoints in cell cycle and allow repair of damaged DNA. Signaling of DNA damage and activation of these pathways are regulated by posttranslational protein modifications. These enzymatic reactions involve mainly phosphorylation, ubiquitination and sumoylation. Recently it was shown that ubiquitination of damaged chromatin is a prerequisite for sumoylation of tumor supressors BRCA1 and 53BP1. Failure in DNA damage recognizing mechanisms caused by disorders such as modifications or mutations of 53BP1 and BRCA1 genes can lead to subsequent disruption of genomic integrity and then a high risk for selection of cell clones with tumorigenic potencial. Current research is focused on regulation of posttranslational...
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Tau protein, a biomarker of Alzheimer's disease: in vitro phosphorylation and tau-reactive antibodies characterization
Hromádková, Lenka ; Bílková, Zuzana (advisor) ; Fialová, Lenka (referee) ; Krejsek, Jan (referee)
Tau protein, a microtubule-associated protein localized in axonal projections of neurons, is a key molecule in the pathology of Alzheimer's disease (AD), the most common cause of dementia in the elderly population. Tau belongs to the group of natively unfolded proteins without globular structure and is prone to numerous posttranslational modifications (PTMs). Under pathological conditions, abnormal PTMs and misfolding of tau protein occurs and leads to oligomerization and aggregation into paired helical filaments forming neurofibrillary tangles, the histopathological hallmark of AD. Currently available drugs applied in AD treatment can only slow the disease progression and those, which halt the AD-specific neurodegenerative processes, are still missing. Very promising and evolving therapeutic approach is immunotherapy, and even immunomodulation by administration of intravenous immunoglobulin (IVIG) products, a reservoir of natural antibodies from the plasma of healthy donors, has been already tested. The discovery of naturally occurring antibodies directed to tau (nTau-Abs) in body fluids of both AD and healthy subjects and their presence in IVIG begin the investigation of their therapeutic potential. Considering a wide range of possible modifications of tau and of various tau species (oligomers,...
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Regulatory mechanisms of WNT signalling
Pospíchalová, Vendula ; Kořínek, Vladimír (advisor) ; Trka, Jan (referee) ; Bryja, Josef (referee)
AB T mu hom dise β sign mu liga stab tran sign T the focu disc cate of t cell targ the inte con sec I sign BSTRACT The Wnt si lticellular o meostasis. A eases, most β-catenin is nalling). In ltiprotein c ands when t bilized and nscription f nalling is tig This thesis knowledge uses on seq cusses the enin signall the Wnt pa ls of intest geted mous thesis des eraction wit nditional Hi retory cell t In conclusi nalling path T ignalling pa organisms Accordingly notably can s a central m n unstimula complex and they engage d transloca factors and ghtly regula is based on e of the reg quential po positive ro ling outcom athway whic tinal epithe e strains th scribes unp th members ic1 deletion types and en ion, our fin hway in dev athway is o ensuring s y, mutations ncer. mediator of ated cells d degraded e their recep tes to the to drive th ated at vario n four origin gulation of sttranslation ole of nucle me. The third ch reduces lium. Final at enable st ublished da s of the Wn n in the inte nhanced tum ndings contr velopment an one of the m successful s in the pat f canonical W β-catenin d in the pro ptors, degrad nucleus t he transcrip ous levels b nal articles f the Wnt s nal process ear protein d study repo the levels o lly, the las tudying the ata on the nt pathway, estinal epith mourigenesi ributed to t...
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The role of posttranslational modifications in action of bacterial toxins
Hudáčková, Kristýna ; Mašín, Jiří (advisor) ; Večerek, Branislav (referee)
Posttranslational modifications of proteins are a widespread mechanisms used by both prokaryotic and eukaryotic cells for increase the diversity of the proteome by the addition of functional groups, proteins, proteolytic cleavage of regulatory subunits, or degradation of entire proteins. These modifications include for example phosphorylation, glycosylation, acetylation, lipidation, ubiquitination or proteolysis and affect almost all aspects of cell biology and pathogenesis. Toxins produced by microorganisms are important virulence factors. Many of these bacterial toxins use posttranslational modification for their activation, as for example listeriolysin O, toxins of Bacillus anthracis or clostridial toxins. Large group of bacterial toxins activated by fatty acid are RTX (from Repeats-in-ToXin) toxins of Gram-negative pathogens, including Bordetella pertussis adenylate cyclase toxin or α-hemolysin secreted by uropathogenic Escherichia coli.
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Regulatory mechanisms of WNT signalling
Pospíchalová, Vendula
AB T mu hom dise β sign mu liga stab tran sign T the focu disc cate of t cell targ the inte con sec I sign BSTRACT The Wnt si lticellular o meostasis. A eases, most β-catenin is nalling). In ltiprotein c ands when t bilized and nscription f nalling is tig This thesis knowledge uses on seq cusses the enin signall the Wnt pa ls of intest geted mous thesis des eraction wit nditional Hi retory cell t In conclusi nalling path T ignalling pa organisms Accordingly notably can s a central m n unstimula complex and they engage d transloca factors and ghtly regula is based on e of the reg quential po positive ro ling outcom athway whic tinal epithe e strains th scribes unp th members ic1 deletion types and en ion, our fin hway in dev athway is o ensuring s y, mutations ncer. mediator of ated cells d degraded e their recep tes to the to drive th ated at vario n four origin gulation of sttranslation ole of nucle me. The third ch reduces lium. Final at enable st ublished da s of the Wn n in the inte nhanced tum ndings contr velopment an one of the m successful s in the pat f canonical W β-catenin d in the pro ptors, degrad nucleus t he transcrip ous levels b nal articles f the Wnt s nal process ear protein d study repo the levels o lly, the las tudying the ata on the nt pathway, estinal epith mourigenesi ributed to t...
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Plant tubulin code
Ničová, Klára ; Schwarzerová, Kateřina (advisor) ; Cvrčková, Fatima (referee)
Microtubules, which are made of polymers of α- and β-tubulin, are an integral part of the cytoskeleton. Both types of tubulin share a considerable sequential homology across eukaryotic organisms. Tubulins are encoded by relatively large gene families. The expression of these genes produces different tubulin isotypes, some of which may exhibit different properties. Tubulin isotypes can be further posttranslationally modified. The best known posttranslational modifications of tubulin include acetylation, phosphorylation, tyrosination, polyglutamylation and polyglycylation. The tubulin code arises from the combination of expression of different tubulin isotypes and their posttranslational modifications. As a consequence, microtubules in cells can be composed of a "mixture" of different tubulins with distinct functions and properties. Even though the existence of the tubulin code has been proven in every model organism, plants included, the precise understanding of the meaning of microtubules being composed of different tubulins is still subjected to research. Much of the research on the tubulin code has been carried out on animal models. In contrast, relatively little is known about the existence of the tubulin code in plants. This theses summarizes current knowledge on the localization and regulation...
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Tau protein, a biomarker of Alzheimer's disease: in vitro phosphorylation and tau-reactive antibodies characterization
Hromádková, Lenka ; Bílková, Zuzana (advisor) ; Fialová, Lenka (referee) ; Krejsek, Jan (referee)
Tau protein, a microtubule-associated protein localized in axonal projections of neurons, is a key molecule in the pathology of Alzheimer's disease (AD), the most common cause of dementia in the elderly population. Tau belongs to the group of natively unfolded proteins without globular structure and is prone to numerous posttranslational modifications (PTMs). Under pathological conditions, abnormal PTMs and misfolding of tau protein occurs and leads to oligomerization and aggregation into paired helical filaments forming neurofibrillary tangles, the histopathological hallmark of AD. Currently available drugs applied in AD treatment can only slow the disease progression and those, which halt the AD-specific neurodegenerative processes, are still missing. Very promising and evolving therapeutic approach is immunotherapy, and even immunomodulation by administration of intravenous immunoglobulin (IVIG) products, a reservoir of natural antibodies from the plasma of healthy donors, has been already tested. The discovery of naturally occurring antibodies directed to tau (nTau-Abs) in body fluids of both AD and healthy subjects and their presence in IVIG begin the investigation of their therapeutic potential. Considering a wide range of possible modifications of tau and of various tau species (oligomers,...
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Role of glycosylation of ionotropic glutamate receptors in mammalian neurons
Danačíková, Šárka ; Horák, Martin (advisor) ; Kriška, Ján (referee)
Glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. There are two distinct types of glutamate receptors, ionotropic and metabotropic, present in the mammalian excitatory synapses. My thesis is focused on the ionotropic glutamate receptors, which play critical roles in learning and memory formation. The main subtypes of ionotropic glutamate receptors are α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate receptors. All types of the ionotropic glutamate receptors, which are assembled as tetramers, contain many glycosylation sites, which can be modified by glycans or monosaccharides. The glycans and monosaccharides attached to the ionotropic glutamate receptors have been shown to regulate key processes such as folding of the subunits, transport to the cell surface as well as their functional properties. Recent literature also suggests that many neurological and psychiatric disorders such as schizophrenia exhibit abnormal glycosylation of ionotropic glutamate receptors. Thus, understanding of the molecular mechanisms, which regulate the glycosylation of the ionotropic glutamate receptors, may be important for developing new therapies for the patients with altered functioning of the glutamatergic synapses in the...
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