Developmental Diseases of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
SW is due to a somatic mutation in the GNAQ gene in skin and meninges. GNAQ encodes Gaq, a member of the G-protein α subunits that mediate signals between G-protein–coupled receptors and downstream effectors. The mutation results in a reduction in GTPase activity leading to increased signaling activity. It is postulated that dysregulation through G-protein–coupled receptors such as that for endothelin may result in malformed progressively dilated blood vessels, a developmental abnormality of the embryonic vascular plexus in the cephalic mesenchyme adjacent to the telencephalic vesicle. It is hypothesized that there is an abnormal regulation of blood vessels, and extracellular matrix expression that produces tortuous abnormal blood vessels in the leptomeninges with sluggish blood flow results in progressive ischemia to the underlying cortex.19
Dopamine Receptors, Signaling Pathways, and Drugs
Nira Ben-Jonathan in Dopamine, 2020
The G proteins belong to a large group of enzymes that function as GTPases. When bound to GTP, G proteins are in an “on,” active conformation, whereas when bound to GDP, they are at an “off,” inactive state [7,8]. The extent of G protein activation by the GPCRs is usually proportional to the concentration of the bound ligand. Within the brain, the GPCRs act primarily, but not exclusively, as mediators of slow neuromodulators rather than fast neurotransmitters [7]. The GPCRs mediate a large variety of neurological events, among which are the chemosensory recognition systems (vision, olfaction, taste), movement regulation, and complex behavioral events. In the periphery, GPCRs mediate the actions of many paracrine peptides and circulating hormones, serving as an integral component of endocrine regulation. In the immune system, GPCRs participate in the control of lymphocyte trafficking and motility and are involved in T-cell activation. There are over 160 orphan GPCRs whose natural ligands are still unknown.
Gene Structure and Expression in Colon Cancer
Leonard H. Augenlicht in Cell and Molecular Biology of Colon Cancer, 2019
A significant limitation of studies on the relationship of ras expression and structural alterations to transformation is our limited understanding of the normal functions of the products of these genes. The ras genes encode proteins of 21 kDa which are localized to the inner surface of the outer cell membrane.49 These proteins exhibit GTP-binding activity and GTPase activity. GTPase activity is lowered by mutations in the P21 molecule which impart transforming activity, 50-53 and sites of mutation which are associated with transforming activity are located at the GTP binding site in the three-dimensional structure of the protein.54 However, the extent of reduction in GTPase activity is not directly correlated with transforming activity in vitro,53,55 although these experiments focused on transforming mutations at amino acid positions other than 12. Nucleotide binding and cellular localization are not affected56 by mutation.
Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure
Published in Platelets, 2023
Mohammed M Jalal, Claire S Whyte, Fraser P Coxon, Nicola J Mutch
Platelets are finely tuned to modulate the response to mechanical injury or vascular breach. A crucial characteristic of platelet function is packaging and uptake of cargo that is subsequently released upon platelet activation. Membrane trafficking is also imperative to granule biogenesis and maturation in megakaryocytes and platelets.1 Small guanosine triphosphatases (GTPases)2,3 act as molecular switches cycling between an inactive GDP-bound’ form to an active “GTP-bound” form to regulate effector proteins which are crucial for trafficking events. GTPases localize to the cytosolic face of subcellular vesicles3 and modulate platelet function at several levels including regulation of platelet activation, integrin exposure4,5 and granule secretion.6,7 Rap1 GTPase belongs to the Ras family8 and exists as two isoforms Rap1a and Rap1b, which are encoded by separate genes but share approximately 95% sequence identity. Rap1a and Rap1b function in activation of the integrins αIIbβ3 and β1 and consequently impact on fibrinogen binding, aggregation, and cytoskeletal responses, including spreading.5,9 Rap1b is the predominant isoform Ras family member in platelets10 and plays additional roles over Rap1a in terms of α- granule secretion.4
Rational design, optimization, and biological evaluation of novel α-Phosphonopropionic acids as covalent inhibitors of Rab geranylgeranyl transferase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Joanna Małolepsza, Aleksandra Marchwicka, Remigiusz A. Serwa, Sanna P. Niinivehmas, Olli T. Pentikäinen, Edyta Gendaszewska-Darmach, Katarzyna M. Błażewska
Encouraged by the possible benefits of this approach, we designed first covalent inhibitors of Rab geranylgeranyltransferase, derived from α-phosphonocarboxylates (PCs). RGGT is involved in the post-translational modification of eukaryotic Rab GTPases, the primary regulators of the formation, transport, docking, and fusion of vesicles during membrane transport.8 The dysfunction of Rab GTPases leads to various diseases ranging from infections to cancer.9 RGGT catalyses double prenylation of most Rab GTPases, with the formation of a thioether bond between two C-terminal cysteines and isoprenoid chains derived from geranylgeranyl pyrophosphate. This modification is necessary for the proper functioning of Rab GTPases, making RGGT a potential drug target. RGGT is a heterodimer composed of an α subunit encoded by the RABGGTA gene and a β subunit encoded by the RABGGTB gene.10
Therapeutic effect of statins on airway remodeling during asthma
Published in Expert Review of Respiratory Medicine, 2022
Mashael Alabed, Noha Mousaad Elemam, Rakhee K Ramakrishnan, Narjes Saheb Sharif-Askari, Tarek Kashour, Qutayba Hamid, Rabih Halwani
Statins are considerably one of the most efficient lipid-lowering medications. Their main mechanism of action is through the inhibition of the enzyme β-hydroxy β-methylglutaryl- coenzyme A (HMG-CoA) reductase, which controls the rate-limiting step in the synthesis of cholesterol. Statins inhibit the conversion of HMG-CoA to mevalonate via the mevalonate pathway. This will lead to a decrease in mevalonate’s metabolites including isoprenoids, such as isopentenyl diphosphate (IPP), farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), and sterols, such as squalene and cholesterol. Isoprenoids represent crucial players in the regulation of small GTPases of the Rab, Rho, and Ras families. GTPases are recognized as key molecules that play a role in cell survival, proliferation, differentiation, and immune system regulation [32–34].
Related Knowledge Centers
- Conserved Sequence
- Enzyme
- Guanosine Diphosphate
- Hydrolase
- Hydrolysis
- Nucleotide
- Protein Domain
- Signal Transduction
- Guanosine Triphosphate
- Walker Motifs