gtpase activity
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Author(s):  
Aaron Ramonett ◽  
Eun-A Kwak ◽  
Tasmia Ahmed ◽  
Paola Cruz Flores ◽  
Hannah R. Ortiz ◽  
...  

Drp1 is a key regulator of mitochondrial fission, a large cytoplasmic GTPase recruited to the mitochondrial surface via transmembrane adaptors to initiate scission. While Brownian motion likely accounts for the local interactions between Drp1 and the mitochondrial adaptors, how this essential enzyme is targeted from more distal regions like the cell periphery remains unknown. Based on proteomic interactome screening and cell-based studies, we report that GIPC mediates the actin-based retrograde transport of Drp1 towards the perinuclear mitochondria to enhance fission. Drp1 interacts with GIPC through its atypical C-terminal PDZ-binding motif. Loss of this interaction abrogates Drp1 retrograde transport resulting in cytoplasmic mislocalization and reduced fission despite retaining normal intrinsic GTPase activity. Functionally, we demonstrate that GIPC potentiates the Drp1-driven proliferative and migratory capacity in cancer cells. Together, these findings establish a direct molecular link between altered GIPC expression and Drp1 function in cancer progression and metabolic disorders.


Science ◽  
2021 ◽  
Vol 374 (6564) ◽  
pp. 197-201 ◽  
Author(s):  
Chuanchuan Li ◽  
Alberto Vides ◽  
Dongsung Kim ◽  
Jenny Y. Xue ◽  
Yulei Zhao ◽  
...  

2021 ◽  
Author(s):  
Vladimir Katanaev ◽  
Yonika Larasati ◽  
Mikhail Savitsky ◽  
Alexey Koval ◽  
Gonzalo Solis

Abstract GNAO1 encephalopathy is a rare pediatric disease characterized by motor dysfunction, developmental delay, and epileptic seizures1-3. De novo point mutations in the gene encoding Gαo, the major neuronal G protein, lie at the core of this dominant genetic malady4. Half of the clinical case mutations fall on codons Gly203, Arg209, or Glu246 near the GTP binding/hydrolysis pocket of Gαo1-3. We here show that these pathologic mutations strongly speed up GTP uptake and inactivate GTP hydrolysis by Gαo, resulting in constitutive GTP binding by the G protein. Molecular dynamics simulations indicate that the mutations cause displacement of Gln205, the key to GTP hydrolysis. Decreased interactions with cellular partners including RGS19 suggest that despite the enhanced GTP residence, the mutants fail to fully adopt the activated conformation and thus transmit the signal. Through a high-throughput screening of approved drugs aiming at correction of this core biochemical dysfunction, we identify zinc pyrithione and Zn2+ ions as agents restoring the active conformation, GTPase activity, and cellular interactions of the encephalopathy mutants, with a negligible effect on wild type Gαo. We describe a Drosophila model of GNAO1 encephalopathy and show that dietary zinc supplementation restores the motor function and longevity of the mutant flies. With zinc supplements frequently recommended for diverse human neurological conditions, our work spanning from identification of the core biochemical defect in Gαo mutants and cellular interactions analysis to high-throughput screening and animal validation of the deficiency-correcting drug defines the potential therapy for GNAO1 encephalopathy patients.


2021 ◽  
Author(s):  
Jinhwan Kim ◽  
Yan Cheng ◽  
Yanfeng Li ◽  
Yi Zhang ◽  
Ji Cheng ◽  
...  

Abstract Mitochondria continuously undergo morphologically dynamic processes of fusion and fission to maintain their size, shape, amount, and function; yet the precise molecular mechanisms by which mitochondrial dynamics is regulated remain to be fully elucidated. Here, we report a previous unappreciated but critical role of eukaryotic elongation factor 2 (eEF2) in regulating mitochondrial fission. eEF2, a G-protein superfamily member encoded by EEF2 gene in human, has long been appreciated as a promoter of the GTP-dependent translocation of the ribosome during protein synthesis. We found unexpectedly in several types of cells that eEF2 was not only present in the cytosol but also in the mitochondria. Furthermore, we showed that mitochondrial length was significantly increased when the cells were subjected to silencing of eEF2 expression, suggesting a promotive role for eEF2 in the mitochondrial fission. Inversely, overexpression of eEF2 decreased mitochondrial length, suggesting an increase of mitochondrial fission. Inhibition of mitochondrial fission caused by eEF2 depletion was accompanied by alterations of cellular metabolism, as evidenced by a reduction of oxygen consumption and an increase of oxidative stress in the mitochondria. We further demonstrated that eEF2 and Drp1, a key driver of mitochondrial fission, co-localized at the mitochondria, as evidenced by microscopic observation, co-immunoprecipitation, and GST pulldown assay. Deletion of the GTP binding motif of eEF2 decreased its association with Drp1 and abrogated its effect on mitochondria fission. Moreover, we showed that wild-type eEF2 stimulated GTPase activity of Drp1, whereas deletion of the GTP binding site of eEF2 diminished its stimulatory effect on GTPase activity. This work not only reveals a previously unrecognized function of eEF2 (i.e., promoting mitochondrial fission), but also uncovers the interaction of eEF2 with Drp1 as a novel regulatory mechanism of the mitochondrial dynamics. Therefore, eEF2 warrants further exploration for its potential as a therapeutic target for the mitochondria-related diseases.


Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 886
Author(s):  
Gabriele Trespidi ◽  
Viola Camilla Scoffone ◽  
Giulia Barbieri ◽  
Federica Marchesini ◽  
Aseel Abualsha’ar ◽  
...  

Staphylococcus aureus infections represent a great concern due to their versatility and involvement in different types of diseases. The shortage of available clinical options, especially to treat multiresistant strains, makes the discovery of new effective compounds essential. Here we describe the activity of the previously described cell division inhibitor C109 against methicillin-sensitive and -resistant S. aureus strains. Antibiofilm activity was assessed using microtiter plates, confocal microscopy, and in an in vitro biofilm wound model. The ability of C109 to block FtsZ GTPase activity and polymerization was tested in vitro. Altogether, the results show that the FtsZ inhibitor C109 has activity against a wide range of S. aureus strains and support its use as an antistaphylococcal compound.


2021 ◽  
Author(s):  
Zhonghui Xu ◽  
John Platig ◽  
Sool Lee ◽  
Adel Boueiz ◽  
Rob Chase ◽  
...  

Cigarette smoking accounts for approximately one in five deaths in the United States. Previous genomic studies have primarily focused on gene level differential expression to identify related molecular signatures and pathways, but the genome-wide effects of smoking on alternative isoform regulation and posttranscriptional modulation have not yet been described. We conducted RNA sequencing (RNA-seq) in whole-blood samples of 454 current and 767 former smokers in COPDGene Study. We assessed the association of current smoking with differential expression of genes and isoforms and differential usage of isoforms and exons. At 10% FDR, we detected 3,167 differentially expressed genes, 2,014 differentially expressed isoforms, 945 differentially used isoforms and 160 differentially used exons. Genes containing differentially used isoforms were enriched in biological pathways involving GTPase activity and innate immunity. The majority of these genes were not differentially expressed, thus not identifiable from conventional differential gene expression analysis. Isoform switch analysis revealed for the first time widespread 3-prime UTR lengthening associated with cigarette smoking, where current smokers were found to have higher expression and usage of isoforms with markedly longer 3-prime UTRs. The lengthening of 3-prime UTRs appears to be mediated through alternative usage of distal polyadenylation sites, and these extended 3-prime UTR regions are significantly enriched with functional sequence elements including adenylate-uridylate (AU)-rich elements, microRNA and RNA-protein binding sites. Expression quantitative trait locus analyses on differentially used 3-prime UTRs identified 79 known GWAS variants associated with multiple smoking-related human diseases and traits. Smoking elicits widespread transcriptional and posttranscriptional alterations with disease implications. It induces alternative polyadenylation (APA) events resulting in a switch towards the usage of isoforms with strikingly longer 3-prime UTRs in genes related to multiple biological pathways including GTPase activity and innate immunity. The extended 3-prime UTR regions are enriched with functional sequence elements facilitating post-transcriptional regulation of protein expression and mRNA stability. These findings warrant further studies on APA events as potential biomarkers and novel therapeutic targets for smoking-related diseases.


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