A posttranslational modification of beta-actin contributes to the slow dissociation of the spectrin-protein 4.1-actin complex of irreversibly sickled cells.

Shartava, Archil; Monteiro, Carlos Augusto; Bencsath, F. A.; Schneider, Klaus; Chait, Brian T.; Gussio, Rick; Casoria-Scott, L A; Shah, Arvind; Heuerman, C A; Goodman, Steven R.

doi:10.1083/jcb.128.5.805

Cited by 57 publications

(61 citation statements)

References 64 publications

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“…This observation suggests that a factor contributing to R116Q disease pathology may be increased sensitivity to oxidative stress, especially if inflammation and the attendant production of reactive oxygen species are involved in the dis-ease process. Another well documented case for oxidative damage to actin has been seen in patients with sickle cell disease in which erythrocyte actin undergoes oxidative intramolecular disulfide cross-linking, leading to abnormal cytoskeletal behavior (50).…”

Section: Discussionmentioning

confidence: 99%

Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

Bergeron

Wedemeyer²,

Lee³

et al. 2011

Journal of Biological Chemistry

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Twenty-two missense mutations in ACTA2, which encodes ␣-smooth muscle actin, have been identified to cause thoracic aortic aneurysm and dissection. Limited access to diseased tissue, the presence of multiple unresolvable actin isoforms in the cell, and lack of an animal model have prevented analysis of the biochemical mechanisms underlying this pathology. We have utilized actin from the yeast Saccharomyces cerevisiae, 86% identical to human ␣-smooth muscle actin, as a model. Two of the known human mutations, N115T and R116Q, were engineered into yeast actin, and their effect on actin function in vivo and in vitro was investigated. Both mutants exhibited reduced ability to grow under a variety of stress conditions, which hampered N115T cells more than R116Q cells. Both strains exhibited abnormal mitochondrial morphology indicative of a faulty actin cytoskeleton. In vitro, the mutant actins exhibited altered thermostability and nucleotide exchange rates, indicating effects of the mutations on monomer conformation, with R116Q the most severely affected. N115T demonstrated a biphasic elongation phase during polymerization, whereas R116Q demonstrated a markedly extended nucleation phase. Allele-specific effects were also seen on critical concentration, rate of depolymerization, and filament treadmilling. R116Q filaments were hypersensitive to severing by the actinbinding protein cofilin. In contrast, N115T filaments were hyposensitive to cofilin despite nearly normal binding affinities of actin for cofilin. The mutant-specific effects on actin behavior suggest that individual mechanisms may contribute to thoracic aortic aneurysm and dissection.

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Section: Discussionmentioning

confidence: 99%

Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

Bergeron

Wedemeyer²,

Lee³

et al. 2011

Journal of Biological Chemistry

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“…Actin was purified from erythrocytes (RBC) essentially as described previously (31). Briefly, 40 ml of human blood was obtained by venipuncture in Vacutainer tubes containing 143 USP units of lithium heparin.…”

Section: Antibodiesmentioning

confidence: 99%

Profilin Is Required for Optimal Actin-Dependent Transcription of Respiratory Syncytial Virus Genome RNA

Burke

Mahoney

Almo

et al. 2000

J Virol

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Transcription of human respiratory syncytial virus (RSV) genome RNA exhibited an obligatory need for the host cytoskeletal protein actin. Optimal transcription, however, required the participation of another cellular protein that was characterized as profilin by a number of criteria. The amino acid sequence of the protein, purified on the basis of its transcription-optimizing activity in vitro, exactly matched that of profilin. RSV transcription was inhibited 60 to 80% by antiprofilin antibody or poly-L-proline, molecules that specifically bind profilin. Native profilin, purified from extracts of lung epithelial cells by affinity binding to a poly-Lproline matrix, stimulated the actin-saturated RSV transcription by 2.5-to 3-fold. Recombinant profilin, expressed in bacteria, stimulated viral transcription as effectively as the native protein and was also inhibited by poly-L-proline. Profilin alone, in the absence of actin, did not activate viral transcription. It is estimated that at optimal levels of transcription, every molecule of viral genomic RNA associates with approximately the following number of protein molecules: 30 molecules of L, 120 molecules of phosphoprotein P, and 60 molecules each of actin and profilin. Together, these results demonstrated for the first time a cardinal role for profilin, an actin-modulatory protein, in the transcription of a paramyxovirus RNA genome.Human respiratory syncytial virus (RSV) is a major pathogen of the lower respiratory tracts of young infants (7). RSV belongs to the Pneumovirus genus within the Paramyxoviridae family. Like other members of this family, RSV has a nonsegmented, negative-strand RNA genome. The RSV genes and genome organization are unique among paramyxoviruses in many respects; the order of genes on the 15,222-kb RSV genomic RNA is 3Ј-(leader)-NS1-NS2-N-P-M-SH-G-F-M2-L-(trailer)-5Ј (14). The RSV nucleocapsid core consists of the viral genomic RNA wrapped with N protein (called the N-RNA template), the phosphoprotein P, the transcription elongation factor M2, and the major subunit of the RNA-dependent RNA polymerase, L (5, 9, 17, 21).As part of our ongoing investigation of the mechanisms of RSV gene expression, we have embarked on the characterization of the various components of the RSV RNA transcription machinery. Our initial studies showed that the viral nucleocapsid core alone was incapable of transcription in vitro; however, the addition of uninfected cell extract restored transcriptional activity (1). Subsequent fractionation of the cell extract revealed that cellular actin is both necessary and sufficient to reconstitute in vitro transcription (5). While that study constituted the first detailed report of a cytoskeletal protein acting as a bona fide transcription factor for RSV, it remained unknown whether actin-modulatory proteins played any role in the process. In the same study, however, we demonstrated that actin alone did not activate viral transcription to the same degree as the whole-cell lysate did. Thus, it was proposed that at least one ...

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“…In actin Cysteine 374 is the most susceptible to oxidation, according to Takashi (1979). Investigations with erythrocytes from patients suffering sickle cell anemina, demonstrated that these cells posses actin molecules oxidised and forming intramolecular disulphide bonds between C284-C373 (Shartava et al, 1995(Shartava et al, , 1997Bencsath et al, 1996). This modification correlates with a decrease in actin polymerisation rates.…”

Section: Actin Cytoskeleton Organisationmentioning

confidence: 99%

Signalling Oxidative Stress in Saccharomyces cerevisiae

Torre-Ruiz¹,

Serrano²,

Petkova³

et al. 2012

Oxidative Stress - Molecular Mechanisms and Biological Effects

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A posttranslational modification of beta-actin contributes to the slow dissociation of the spectrin-protein 4.1-actin complex of irreversibly sickled cells.

Cited by 57 publications

References 64 publications

Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

Profilin Is Required for Optimal Actin-Dependent Transcription of Respiratory Syncytial Virus Genome RNA

Signalling Oxidative Stress in Saccharomyces cerevisiae

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