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Elyse S Fischer Conny W H Yu Dom Bellini Stephen H McLaughlin Christian M Orr Armin Wagner Stefan M V Freund David Barford 《EMBO reports》2021,22(7)
During metaphase, in response to improper kinetochore‐microtubule attachments, the spindle assembly checkpoint (SAC) activates the mitotic checkpoint complex (MCC), an inhibitor of the anaphase‐promoting complex/cyclosome (APC/C). This process is orchestrated by the kinase Mps1, which initiates the assembly of the MCC onto kinetochores through a sequential phosphorylation‐dependent signalling cascade. The Mad1‐Mad2 complex, which is required to catalyse MCC formation, is targeted to kinetochores through a direct interaction with the phosphorylated conserved domain 1 (CD1) of Bub1. Here, we present the crystal structure of the C‐terminal domain of Mad1 (Mad1CTD) bound to two phosphorylated Bub1CD1 peptides at 1.75 Å resolution. This interaction is mediated by phosphorylated Bub1 Thr461, which not only directly interacts with Arg617 of the Mad1 RLK (Arg‐Leu‐Lys) motif, but also directly acts as an N‐terminal cap to the CD1 α‐helix dipole. Surprisingly, only one Bub1CD1 peptide binds to the Mad1 homodimer in solution. We suggest that this stoichiometry is due to inherent asymmetry in the coiled‐coil of Mad1CTD and has implications for how the Mad1‐Bub1 complex at kinetochores promotes efficient MCC assembly. 相似文献
124.
Raybaud A Dodier Y Bissonnette P Simoes M Bichet DG Sauvé R Parent L 《The Journal of biological chemistry》2006,281(51):39424-39436
The putative hinge point revealed by the crystal structure of the MthK potassium channel is a glycine residue that is conserved in many ion channels. In high voltage-activated (HVA) Ca(V) channels, the mid-S6 glycine residue is only present in IS6 and IIS6, corresponding to G422 and G770 in Ca(V)1.2. Two additional glycine residues are found in the distal portion of IS6 (Gly(432) and Gly(436) in Ca(V)1.2) to form a triglycine motif unique to HVA Ca(V) channels. Lethal arrhythmias are associated with mutations of glycine residues in the human L-type Ca(2+) channel. Hence, we undertook a mutational analysis to investigate the role of S6 glycine residues in channel gating. In Ca(V)1.2, alpha-helix-breaking proline mutants (G422P and G432P) as well as the double G422A/G432A channel did not produce functional channels. The macroscopic inactivation kinetics were significantly decreased with Ca(V)1.2 wild type > G770A > G422A congruent with G436A > G432A (from the fastest to the slowest). Mutations at position Gly(432) produced mostly nonfunctional mutants. Macroscopic inactivation kinetics were markedly reduced by mutations of Gly(436) to Ala, Pro, Tyr, Glu, Arg, His, Lys, or Asp residues with stronger effects obtained with charged and polar residues. Mutations within the distal GX(3)G residues blunted Ca(2+)-dependent inactivation kinetics and prevented the increased voltage-dependent inactivation kinetics brought by positively charged residues in the I-II linker. In Ca(V)2.3, mutation of the distal glycine Gly(352) impacted significantly on the inactivation gating. Altogether, these data highlight the role of the GX(3)G motif in the voltage-dependent activation and inactivation gating of HVA Ca(V) channels with the distal glycine residue being mostly involved in the inactivation gating. 相似文献
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Francesco Chiappelli Paul Shapshak Deborah Commins Elyse Singer Alireza Minagar Oluwadayo Oluwadara Paolo Prolo Andras J Pellionisz 《Bioinformation》2008,3(1):47-52
Epigenetics studies factors related to the organism and environment that modulate inheritance from generation to generation. Molecular epigenetics examines non-coding DNA (ncdDNA) vs. coding DNA (cdDNA), and
pertains to every domain of physiology, including immune and brain function. Molecular cartography, including genomics, proteomics, and interactomics, seeks to recognize and to identify the multi-faceted and
intricate array of interacting genes and gene products that characterize the function and specialization of each individual cell in the context of cell-cell interaction, tissue, and organ function. Molecular
cartography, epigenetics, and chromatin assembly, repair and remodeling (CARR), which, together with the RNA interfering signaling complex (RISC), is responsible for much of the control and regulation of gene
expression, intersect.We describe current and ongoing studies aimed to apply these overlapping areas of research, CARR and RISC, to a novel understanding of the immuno-neuropathology of HIV-1 infection, as an example. Taken together,
the arguments presented here lead to a novel working hypothesis of molecular immune epigenetics as it pertains to HIV/AIDS, and the immunopathology of HIV-1-infected CD4+ cells. Specifically, we discuss these views
in the context of the structure-function relationship of chromatin, the cdDNA/ncdDNA ratio, and possible nucleotide divergence in the untranslated regions (UTRs) of mature mRNA intronic and intergenic DNA sequences,
and putative catastrophic consequences for immune surveillance and the preservation of health in HIV/AIDS. Here, we discuss the immunopathology of HIV Infection, with emphasis on CARR in cellular, humoral and molecular
immune epigenetics. 相似文献
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Minagar A Commins D Alexander JS Hoque R Chiappelli F Singer EJ Nikbin B Shapshak P 《Molecular diagnosis & therapy》2008,12(1):25-43
The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-associated dementia (HAD; also known as AIDS dementia and HIV encephalopathy). HAD is the most significant and devastating central nervous system (CNS) complications associated with HIV infection. Despite recent advances in our knowledge of the clinical features, pathogenesis, and neurobiological aspects of HAD, it remains a formidable scientific and therapeutic challenge. An understanding of the mechanisms of HIV neuroinvasion, CNS proliferation, and HAD pathogenesis provide a basis for the interpretation of the diagnostic features of HAD and its milder form, HIV-associated minor cognitive/motor disorder (MCMD). Current diagnostic strategies are associated with significant limitations, but it is hoped that the use of biomarkers may assist researchers and clinicians in predicting the onset of the disease process and in evaluating the effects of new therapies. 相似文献
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Metabolic processes involved in repair of Escherichia coli cells damaged by exposure to acid mine water.
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Escherichia coli was stressed by exposure to filter-sterilized acid mine water. Synthetic processes required for repair of sublethally injured survivors were studied by the addition of specific metabolic inhibitors to a resuscitation broth. Inhibitors of protein, RNA, DNA, lipid, and peptidoglycan synthesis as well as uncouplers and inhibitors of electron transport and ATPase activity were used. Acid mine water injury was severe, causing damage to the outer and cytoplasmic membranes. Repair of sublethally injured cells required protein, RNA, and lipid synthesis as well as a proton motive force. 相似文献