Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
The last subgroup of mitochondrial diseases with nucleotide pool perturbations is the one resulting from defective transport between mitochondria and the cytosol. Here two main defects can be described – mutations in SLC25A4 (formerly called ANT1) and MPV 17. SLC25A4 (4q35.1) encoding adenosine nucleotides translocator, an inner mitochondrial membrane protein responsible for the transport of ATP, produced in the process of oxidative respiration, from mitochondrial matrix to intermembrane space and ADP, necessary as a substrate for ATP production, from intermembrane space to mitochondrial matrix. Mutations in SLC25A4 were in fact the first described defect of mtDNA maintenance presenting as autosomal dominant PEO43. The dominance of SLC25A4 mutations can be easily explained by the structure of the adenine nucleotide translocator. The protein forms a homodimer. When proteins produced from one of the alleles are defective it can be predicted that up to 3/4 of translocators can have improper structure and function. Recently the third player in this group has appeared: AGK (7q34) gene encoding acylglicerol synthase. It is necessary for membrane lipids synthesis and therefore influences mitochondrial membrane composition. It seems that mutations in AGK lead to improper ANT1 assembly, as the nucleotide translocator is bound to the inner membrane phosphatidic acid and cardiolipin44.
PCR primer design for detection of SNPs in SLC22A1 rs683369 encoding OCT1 as the main transporter of metformin
Elida Zairina, Junaidi Khotib, Chrismawan Ardianto, Syed Azhar Syed Sulaiman, Charles D. Sands, Timothy E. Welty in Unity in Diversity and the Standardisation of Clinical Pharmacy Services, 2017
Intramolecular and intermolecular interactions will produce primer secondary structures in the form of hairpins as well as dimmers, which potentially reduce amplification product by affecting the primer flanking region during the amplification process. The designed primer had a significantly different Tm from that of hairpin, in which the Tm of forward primer was 57.7°C with 19.3°C hairpin Tm and the reverse primer had 56.7°C Tm with 33.4°C hairpin Tm; therefore, hairpin formation was less likely to occur, and this condition remained tolerable. Dimers in a primer can be homodimer or heterodimer. A homodimer is formed when a primer binds to another primer of the same type (reverse-reverse or forward-forward), while a hetero dimer is obtained when a primer binds to its pair (reverse-forward)(PCR Primer Design Guidelines n.d.). Table 1 shows a significant difference in ΔG between one primer and another compared to ΔG of the binding between a primer and target sequence; this condition can be tolerated.
PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
PML/RARa behaves as a potent repressor of the RA signalling pathway (Fig. 10.1). The traditional model postulated that PML/RARa acted as a constitutive transcriptional repressor that altered the normal RARa signalling in APL cells, as the chimeric protein is unable to respond to physiological fluctuations of RA [42]. The transcriptional repression was shown to be the consequence of greatly enhanced binding to the SMRT/NCoR co-repressors and HDACs [23]. PML/RARa homodimerises and binds to DNA at the RARE sites even in the absence of its normal heterodimeric partner RXR. The homodimerisation is thought to enhance the binding of the physiological RARa interactors. Simplistically, enhanced corepressors binding depends upon the fact that the homodimer harbours two co-repressor docking sites and not just one as in RXR/RARa heterodimer, leading to a change in stoichiometry of association of PML/RARa with co-repressors and chromatin modifiers [39]. However, in addition, the formation of homodimers leads to the creation of novel binding interfaces. Histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3 is one of the chimera-specific partners responsible for imposing a heterochromatin-like structure on target genes, thereby establishing permanent transcriptional silencing [9]. Similarly, polycomb repressive complex 2 (PRC2) represents another example of a new PML/RARa interactor. It has been found that PRC2 is recruited to tumour suppressor genes causing and maintaining their silencing during the initial steps of PML/RARa driven leukaemogenesis [57].
Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy
Published in Journal of Drug Targeting, 2019
PD-1 is a 55 kDa type I surface transmembrane glycoprotein receptor consisting of 288 amino acids [56]. The protein contains four domains: the extracellular domain is an IgV-like immunoglobulin superfamily domain, the cytoplasmic domain consisting of 95 residues, a handle consisting of 22 residues and a transmembrane domain. The cytoplasmic domain contains two tyrosine-dependent immune receptor signalling motifs, the immunoreceptor tyrosine-inhibitory motif (ITIM) and the immunoreceptor tyrosine-based switch motif (ITSM). Unlike other family members of B7-CD28, PD-1 is usually present as a monomer, not a homodimer. The two ligands PD-L1 and PD-L2 of PD-1 are both transmembrane proteins consisting of 290 and 268 amino acid residues and belong to the B7 ligand family, with 34% homology. In addition, the two have a common structural basis, that is, their extracellular domain consists of two side-by-side domains, one IgV-like region and one IgC-like region, which binds directly to PD-1. The binding of PD-L1 or PD-L2 to PD-1 initiates antigen receptor signalling transduction, leading to the phosphorylation of two tyrosine signal motifs in the PD-1 cytoplasmic domain and thereby activating downstream signalling pathways and destroying the T cell metabolism and releasing other signal factors, ultimately undoing the immune function of T cells [57]. In addition, PD-L1/PD-L2 has a conserved intracellular domain consisting of 30 residues whose function is unknown [58].
Unveiling the interaction profile of rosmarinic acid and its bioactive substructures with serum albumin
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Christina Papaemmanouil, Maria V. Chatziathanasiadou, Christos Chatzigiannis, Eleni Chontzopoulou, Thomas Mavromoustakos, Simona Golic Grdadolnik, Andreas G. Tzakos
Bovine serum albumin (BSA) homodimer crystal structure was downloaded from the Protein Data Bank (https://www.rcsb.org/). The downloaded structure of BSA (PDB ID: 4F5S) constitutes the crystal structure of the apoenzyme – protein. BSA complexes with various bioactive molecules were not used in the study as the ligands deviated structurally with those under study. The homodimer protein was prepared using Maestro’s Protein Preparation Wizard. During this preparation, missing loops and side chains were fixed using Prime algorithm. Water molecules beyond 5 Å from het groups were deleted, disulphide bonds among Cys residues were created and hydrogens were added to the crystal structure. Overlapping atoms were minimised and different alternate positions of side chains were committed to a single one. Chain B of each homodimer was deleted to accelerate docking process. PROPKA was used to identify the protonation states of amino acids at neutral pH and OPLS3 force field was applied in order to minimise hydrogen atoms of the protein.
An emerging role of interleukin-23 in rheumatoid arthritis
Published in Immunopharmacology and Immunotoxicology, 2019
Na Yuan, Guimei Yu, Di Liu, Xiancheng Wang, Ling Zhao
IL-23 is a disulphide-linked heterodimeric cytokine and it is composed of a ‘soluble receptor’ subunit, p40 (also present in IL-12) and a gp130 class of cytokine-like subunit related to IL-12p35, termed as p19 (unique to IL-23) [19]. It is primarily secreted by macrophages and dendritic cells (DC) and, it regulates the differentiation of Th17 cells from native CD4+ T cells. Macrophages and DCs secrete both subunits of IL-23, i.e. p19 and p40 subunits. However, these subunits can exist as a monomer, homodimer, or heterodimer to produce diverse actions [20]. Data from genetically engineered mice and other studies demonstrate the presence of IL-23 receptors (IL-23R) on the surface of lymphoid cells including αβ and γδ T cells, innate lymphoid and myeloid derived cells including DCs, macrophages, and monocytes [21,22]. The cytoplasmic domain of human IL-23R does not possess the kinase activity. However, it possesses seven tyrosine residues that can be phosphorylated to initiate downstream signaling. Although, human and mouse IL-23 share certain biological actions with IL-12, yet these differ in terms of their capacity to stimulate particular populations of memory T cells. The similarity in biological actions of human and mouse IL-23 is attributed to conservation of six (out of seven) human IL-23R tyrosine residues in mouse [23].
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