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Alexey Polonikov Larisa Rymarova Elena Klyosova Anastasia Volkova Iuliia Azarova Olga Bushueva Marina Bykanova Iuliia Bocharova Sergey Zhabin Mikhail Churnosov Vitaliy Laskov Maria Solodilova 《Journal of cellular biochemistry》2019,120(10):16467-16482
The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome-wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome-wide associated loci for IS were done using Taq-Man–based assays and MALDI-TOF mass spectrometry iPLEX platform, respectively. Allele − 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70-0.96; P = 0.016). The model-based multifactor dimensionality reduction method has revealed 21 two-order, 124 three-order, and 474 four-order gene-gene (G×G) interactions models meaningfully (Pperm < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery. 相似文献
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Ho-Won Kang Iuliia Vitko Sang-Soo Lee Edward Perez-Reyes Jung-Ha Lee 《The Journal of biological chemistry》2010,285(5):3271-3281
Cav3.2 T-type channels contain a high affinity metal binding site for trace metals such as copper and zinc. This site is occupied at physiologically relevant concentrations of these metals, leading to decreased channel activity and pain transmission. A histidine at position 191 was recently identified as a critical determinant for both trace metal block of Cav3.2 and modulation by redox agents. His191 is found on the extracellular face of the Cav3.2 channel on the IS3-S4 linker and is not conserved in other Cav3 channels. Mutation of the corresponding residue in Cav3.1 to histidine, Gln172, significantly enhances trace metal inhibition, but not to the level observed in wild-type Cav3.2, implying that other residues also contribute to the metal binding site. The goal of the present study is to identify these other residues using a series of chimeric channels. The key findings of the study are that the metal binding site is composed of a Asp-Gly-His motif in IS3–S4 and a second aspartate residue in IS2. These results suggest that metal binding stabilizes the closed conformation of the voltage-sensor paddle in repeat I, and thereby inhibits channel opening. These studies provide insight into the structure of T-type channels, and identify an extracellular motif that could be targeted for drug development. 相似文献
3.
Iuliia Vitko Aleksandr Shcheglovitov Joel P. Baumgart Imilla I. Arias-Olguín Janet Murbartián Juan Manuel Arias Edward Perez-Reyes 《PloS one》2008,3(10)
Background
The Cavβ subunits of high voltage-activated Ca2+ channels control the trafficking and biophysical properties of the α1 subunit. The Cavβ-α1 interaction site has been mapped by crystallographic studies. Nevertheless, how this interaction leads to channel regulation has not been determined. One hypothesis is that βs regulate channel gating by modulating movements of IS6. A key requirement for this direct-coupling model is that the linker connecting IS6 to the α-interaction domain (AID) be a rigid structure.Methodology/Principal Findings
The present study tests this hypothesis by altering the flexibility and orientation of this region in α12.2, then testing for Cavβ regulation using whole cell patch clamp electrophysiology. Flexibility was induced by replacement of the middle six amino acids of the IS6-AID linker with glycine (PG6). This mutation abolished β2a and β3 subunits ability to shift the voltage dependence of activation and inactivation, and the ability of β2a to produce non-inactivating currents. Orientation of Cavβ with respect to α12.2 was altered by deletion of 1, 2, or 3 amino acids from the IS6-AID linker (Bdel1, Bdel2, Bdel3, respectively). Again, the ability of Cavβ subunits to regulate these biophysical properties were totally abolished in the Bdel1 and Bdel3 mutants. Functional regulation by Cavβ subunits was rescued in the Bdel2 mutant, indicating that this part of the linker forms β-sheet. The orientation of β with respect to α was confirmed by the bimolecular fluorescence complementation assay.Conclusions/Significance
These results show that the orientation of the Cavβ subunit relative to the α12.2 subunit is critical, and suggests additional points of contact between these subunits are required for Cavβ to regulate channel activity. 相似文献4.
5.
Staphylococcus aureus lactate‐ and malate‐quinone oxidoreductases contribute to nitric oxide resistance and virulence
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Nicole A. Spahich Nicholas P. Vitko Lance R. Thurlow Brenda Temple Anthony R. Richardson 《Molecular microbiology》2016,100(5):759-773
Staphylococcus aureus is a Gram‐positive pathogen that resists many facets of innate immunity including nitric oxide (NO·). Staphylococcus aureus NO‐resistance stems from its ability to evoke a metabolic state that circumvents the negative effects of reactive nitrogen species. The combination of l ‐lactate and peptides promotes S. aureus growth at moderate NO‐levels, however, neither nutrient alone suffices. Here, we investigate the staphylococcal malate‐quinone and l ‐lactate‐quinone oxidoreductases (Mqo and Lqo), both of which are critical during NO‐stress for the combined utilization of peptides and l ‐lactate. We address the specific contributions of Lqo‐mediated l ‐lactate utilization and Mqo‐dependent amino acid consumption during NO‐stress. We show that Lqo conversion of l ‐lactate to pyruvate is required for the formation of ATP, an essential energy source for peptide utilization. Thus, both Lqo and Mqo are essential for growth under these conditions making them attractive candidates for targeted therapeutics. Accordingly, we exploited a modelled Mqo/Lqo structure to define the catalytic and substrate‐binding residues.We also compare the S. aureus Mqo/Lqo enzymes to their close relatives throughout the staphylococci and explore the substrate specificities of each enzyme. This study provides the initial characterization of the mechanism of action and the immunometabolic roles for a newly defined staphylococcal enzyme family. 相似文献
6.
Olivia Sveidahl Johansen Tao Ma Jakob Bondo Hansen Lasse Kruse Markussen Renate Schreiber Laia Reverte-Salisa Hua Dong Dan Ploug Christensen Wenfei Sun Thorsten Gnad Iuliia Karavaeva Thomas Svava Nielsen Sander Kooijman Cheryl Cero Oksana Dmytriyeva Yachen Shen Maria Razzoli Shannon L. O’Brien Zachary Gerhart-Hines 《Cell》2021,184(13):3502-3518.e33
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High voltage-activated Ca(2+) channel expression and gating is controlled by their beta subunits. Although the sites of interaction are known at the atomic level, how beta modulates gating remains to be determined. Using a chimeric approach, beta subunit regulation was conferred to a low voltage-activated channel. Regulation was dependent on a rigid linker connecting the alpha(1) interaction domain to IS6. Chimeric channels also revealed a role for IS6 in channel gating. Taken together, these results support a direct coupling model where beta subunits alter movements in IS6 that occur as the channel transits between closed, open, and inactivated states. 相似文献
9.
Helena Jambor Alberto Antonietti Bradly Alicea Tracy L. Audisio Susann Auer Vivek Bhardwaj Steven J. Burgess Iuliia Ferling Magorzata Anna Gazda Luke H. Hoeppner Vinodh Ilangovan Hung Lo Mischa Olson Salem Yousef Mohamed Sarvenaz Sarabipour Aalok Varma Kaivalya Walavalkar Erin M. Wissink Tracey L. Weissgerber 《PLoS biology》2021,19(3)
10.
Azarova Iuliia Klyosova Elena Lazarenko Victor Konoplya Alexander Polonikov Alexey 《Molecular biology reports》2020,47(8):5793-5805
Molecular Biology Reports - Oxidative stress contributes to the pathogenesis of type 2 diabetes (T2D). This study investigated whether single nucleotide polymorphisms (SNPs) at genes encoding... 相似文献