scholarly journals Actin Mutations and Their Role in Disease

2020 ◽  
Vol 21 (9) ◽  
pp. 3371 ◽  
Author(s):  
Francine Parker ◽  
Thomas G. Baboolal ◽  
Michelle Peckham
Keyword(s):  
Actin Polymerization ◽  
Eukaryotic Cells ◽  
Actin Isoforms ◽  
Cardiac Actin ◽  
Mutational Hotspots ◽  
Almost All

Actin is a widely expressed protein found in almost all eukaryotic cells. In humans, there are six different genes, which encode specific actin isoforms. Disease-causing mutations have been described for each of these, most of which are missense. Analysis of the position of the resulting mutated residues in the protein reveals mutational hotspots. Many of these occur in regions important for actin polymerization. We briefly discuss the challenges in characterizing the effects of these actin mutations, with a focus on cardiac actin mutations.

scholarly journals Cardiac and Skeletal Actin Substrates Uniquely Tune Cardiac Myosin Strain-Dependent Mechanics

2018 ◽  
Author(s):  
Yihua Wang ◽  
Katalin Ajtai ◽  
Thomas P. Burghardt
Keyword(s):  
Resistive Load ◽  
Step Size ◽  
Actin Isoforms ◽  
Cardiac Actin ◽  
N Terminus ◽  
Human Adults ◽  
Force Velocity ◽  
Strain Dependent

ABSTRACTNative cardiac ventricular myosin (βmys) translates actin under load by transducing ATP free energy into mechanical work on actin during muscle contraction. Unitary βmys translation of actin is the myosin step-size. In vitro and in vivo βmys regulates contractile force and velocity by remixing 3 different step-sizes with stepping frequencies autonomously adapted to workload. Cardiac and skeletal actin isoforms have a specific 1:4 stoichiometry in normal adult human ventriculum. Human adults with inheritable hypertrophic cardiomyopathy (HCM) up-regulate skeletal actin in ventriculum suggesting that increasing skeletal/cardiac actin stoichiometry also adapts myosin force-velocity to respond to the muscle’s inability to meet demand.Nanometer scale displacement of quantum dot (Qdot) labeled actin under resistive load when impelled by βmys measures single myosin force-velocity in vitro in the Qdot assay. Unitary displacement classification constraints introduced here better separates myosin based signal from background upgrading step-size spatial resolution to the sub-nanometer range. Single βmys force-velocity for skeletal vs cardiac actin substrates was compared using the Qdot assay.Two competing myosin strain-sensitive mechanisms regulate step-size choices dividing mechanical characteristics into low- and high-force regimes. The actin isoforms alter myosin strain-sensitive regulation such that onset of the high-force regime, where a short step-size is a large or major contributor, is offset to higher loads by a unique cardiac ELC N-terminus/cardiac-actin contact at Glu6/Ser358. It modifies βmys force-velocity by stabilizing the ELC N-terminus/cardiac-actin association. Uneven onset of the high-force regime for skeletal vs cardiac actin dynamically changes force-velocity characteristics as skeletal/cardiac actin fractional content increases in diseased muscle.

New workflow for classification of genetic variants’ pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID)

2018 ◽  
Vol 55 (8) ◽  
pp. 530-537 ◽  
Author(s):  
Marielle E Van Gijn ◽  
Isabella Ceccherini ◽  
Yael Shinar ◽  
Ellen C Carbo ◽  
Mariska Slofstra ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Clinical Symptoms ◽  
Inflammatory Diseases ◽  
International Study ◽  
Biological Drugs ◽  
Link Type ◽  
Expert Opinions ◽  
Mutational Hotspots ◽  
Almost All

BackgroundHereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.ObjectivesThis study aimed to obtain an experts’ consensus on the clinical significance of gene variants in four well-known HRF genes: MEFV, TNFRSF1A, NLRP3 and MVK.MethodsWe configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds.ResultsConsensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the MEFV gene.ConclusionApplying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/.

scholarly journals WASP and SCAR are evolutionarily conserved in actin-filled pseudopod-based motility

2017 ◽  
Vol 216 (6) ◽  
pp. 1673-1688 ◽  
Author(s):  
Lillian K. Fritz-Laylin ◽  
Samuel J. Lord ◽  
R. Dyche Mullins
Keyword(s):  
Actin Polymerization ◽  
Eukaryotic Cells ◽  
Human Neutrophils ◽  
Evolutionary Relationships ◽  
Actin Assembly ◽  
Complex Environments ◽  
Clear Trend ◽  
Cell Crawling ◽  
Evolutionarily Conserved ◽  
Underlying Mechanisms

Diverse eukaryotic cells crawl through complex environments using distinct modes of migration. To understand the underlying mechanisms and their evolutionary relationships, we must define each mode and identify its phenotypic and molecular markers. In this study, we focus on a widely dispersed migration mode characterized by dynamic actin-filled pseudopods that we call “α-motility.” Mining genomic data reveals a clear trend: only organisms with both WASP and SCAR/WAVE—activators of branched actin assembly—make actin-filled pseudopods. Although SCAR has been shown to drive pseudopod formation, WASP’s role in this process is controversial. We hypothesize that these genes collectively represent a genetic signature of α-motility because both are used for pseudopod formation. WASP depletion from human neutrophils confirms that both proteins are involved in explosive actin polymerization, pseudopod formation, and cell migration. WASP and WAVE also colocalize to dynamic signaling structures. Moreover, retention of WASP together with SCAR correctly predicts α-motility in disease-causing chytrid fungi, which we show crawl at >30 µm/min with actin-filled pseudopods. By focusing on one migration mode in many eukaryotes, we identify a genetic marker of pseudopod formation, the morphological feature of α-motility, providing evidence for a widely distributed mode of cell crawling with a single evolutionary origin.

scholarly journals Bacterial Actin-Specific Endoproteases Grimelysin and Protealysin as Virulence Factors Contributing to the Invasive Activities of Serratia

2020 ◽  
Vol 21 (11) ◽  
pp. 4025 ◽  
Author(s):  
Sofia Khaitlina ◽  
Ekaterina Bozhokina ◽  
Olga Tsaplina ◽  
Tatiana Efremova
Keyword(s):  
Escherichia Coli ◽  
Actin Polymerization ◽  
Membrane Vesicles ◽  
Eukaryotic Cells ◽  
Bacterial Invasion ◽  
Functional Activities ◽  
Serratia Proteamaculans ◽  
Serratia Grimesii ◽  
Bacterial Protease ◽  
Reversible Loss

The article reviews the discovery, properties and functional activities of new bacterial enzymes, proteases grimelysin (ECP 32) of Serratia grimesii and protealysin of Serratia proteamaculans, characterized by both a highly specific “actinase” activity and their ability to stimulate bacterial invasion. Grimelysin cleaves the only polypeptide bond Gly42-Val43 in actin. This bond is not cleaved by any other proteases and leads to a reversible loss of actin polymerization. Similar properties were characteristic for another bacterial protease, protealysin. These properties made grimelysin and protealysin a unique tool to study the functional properties of actin. Furthermore, bacteria Serratia grimesii and Serratia proteamaculans, producing grimelysin and protealysin, invade eukaryotic cells, and the recombinant Escherichia coli expressing the grimelysin or protealysins gene become invasive. Participation of the cellular c-Src and RhoA/ROCK signaling pathways in the invasion of eukaryotic cells by S. grimesii was shown, and involvement of E-cadherin in the invasion has been suggested. Moreover, membrane vesicles produced by S. grimesii were found to contain grimelysin, penetrate into eukaryotic cells and increase the invasion of bacteria into eukaryotic cells. These data indicate that the protease is a virulence factor, and actin can be a target for the protease upon its translocation into the host cell.

scholarly journals A codon change in beta-tubulin which drastically affects microtubule structure in Drosophila melanogaster fails to produce a significant phenotype in Saccharomyces cerevisiae.

1991 ◽  
Vol 11 (9) ◽  
pp. 4726-4731 ◽  
Author(s):  
V Praitis ◽  
W S Katz ◽  
F Solomon
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drosophila Melanogaster ◽  
Eukaryotic Cells ◽  
Tubulin Gene ◽  
Beta Tubulin ◽  
Cell Biol ◽  
Codon Change ◽  
Almost All ◽  
Beta Tubulin Gene ◽  
Microtubule Structure

The relative uniformity of microtubule ultrastructure in almost all eukaryotic cells is thought to be a consequence of the conserved elements of tubulin sequence. In support of this idea, a mutation in a beta-tubulin gene of Drosophila melanogaster, occurring at a highly conserved position, produces U-shaped microtubules, suggesting a defect in either nucleation or packing during assembly (M. T. Fuller, J. H. Caulton, J. A. Hutchens, T. C. Kaufman, and E. C. Raff, J. Cell Biol. 104:385-394, 1987, and J. E. Rudolph, M. Kimble, H. D. Hoyle, M. A. Subler, and E. C. Raff, Mol. Cell. Biol. 7:2231-2242, 1987). Surprisingly, we find that introducing the same mutation into the sole beta-tubulin gene of Saccharomyces cerevisiae has virtually no consequences for microtubule structure or function in that organism.

Thromboxane-induced actin polymerization in hypoxic neonatal pulmonary arterial myocytes involves Cdc42 signaling

2014 ◽  
Vol 307 (11) ◽  
pp. L877-L887 ◽  
Author(s):  
Jena Fediuk ◽  
Anurag S. Sikarwar ◽  
Nora Nolette ◽  
Shyamala Dakshinamurti
Keyword(s):  
Rho Gtpases ◽  
Laser Scanning ◽  
Actin Polymerization ◽  
Filamentous Actin ◽  
Actin Isoforms ◽  
Pi3k Activity ◽  
Laser Scanning Cytometry ◽  
Pulmonary Arterial ◽  
P21 Activated Kinase ◽  
Syndrome Protein

In hypoxic pulmonary arterial (PA) myocytes, challenge with thromboxane mimetic U46619 induces marked actin polymerization and contraction, phenotypic features of persistent pulmonary hypertension of the newborn (PPHN). Rho GTPases regulate the actin cytoskeleton. We previously reported that U46619-induced actin polymerization in hypoxic PA myocytes occurs independently of the RhoA pathway and hypothesized involvement of the Cdc42 pathway. PA myocytes grown in normoxia or hypoxia for 72 h were stimulated with U46619, then analyzed for Rac/Cdc42 activation by affinity precipitation, phosphatidylinositide-3-kinase (PI3K) activity by phospho-Akt, phospho-p21-activated kinase (PAK) by immunoblot, and association of Cdc42 with neuronal Wiskott Aldrich Syndrome protein (N-WASp) by immunoprecipitation. The effect of Rac or PAK inhibition on filamentous actin was quantified by laser-scanning cytometry and by cytoskeletal fractionation; effects of actin-modifying agents were measured by isometric myography. Basal Cdc42 activity increased in hypoxia, whereas Rac activity decreased. U46619 challenge increased Cdc42 and Rac activity in hypoxic cells, independently of PI3K. Hypoxia increased phospho-PAK, unaltered by U46619. Association of Cdc42 with N-WASp decreased in hypoxia but increased after U46619 exposure. Hypoxia doubled filamentous-to-globular ratios of α- and γ-actin isoforms. Jasplakinolide stabilized γ-filaments, increasing force; cytochalasin D depolymerized all actin isoforms, decreasing force. Rac and PAK inhibition decreased filamentous actin in tissues although without decrease in force. Rho inhibition decreased myosin phosphorylation and force. Hypoxia induces actin polymerization in PA myocytes, particularly increasing filamentous α- and γ-actin, contributing to U46619-induced contraction. Hypoxic PA myocytes challenged with a thromboxane mimetic polymerize actin via the Cdc42 pathway, reflecting increased Cdc42 association with N-WASp. Mechanisms regulating thromboxane-mediated actin polymerization are potential targets for future PPHN pharmacotherapy.

scholarly journals WASP and SCAR are evolutionarily conserved in actin-filled pseudopod-based motility

2016 ◽  
Author(s):  
Lillian K. Fritz-Laylin ◽  
Samuel J. Lord ◽  
R. Dyche Mullins
Keyword(s):  
Actin Polymerization ◽  
Eukaryotic Cells ◽  
Human Neutrophils ◽  
Evolutionary Relationships ◽  
Actin Assembly ◽  
Complex Environments ◽  
Clear Trend ◽  
Cell Crawling ◽  
Evolutionarily Conserved ◽  
Underlying Mechanisms

AbstractDiverse eukaryotic cells crawl through complex environments using distinct modes of migration. To understand the underlying mechanisms and their evolutionary relationships, we must define each mode, and identify its phenotypic and molecular markers. Here, we focus on a widely dispersed migration mode characterized by dynamic, actin-filled pseudopods that we call “α-motility.” Mining genomic data reveals a clear trend: only organisms with both WASP and SCAR/WAVE—activators of branched actin assembly—make actin-filled pseudopods. While SCAR has been shown to drive pseudopod formation, WASP’s role in this process is controversial. We hypothesize that these genes together represent a genetic signature of α-motility, because both are used for pseudopod formation. WASP depletion from human neutrophils confirms that both proteins are involved in explosive actin polymerization, pseudopod formation, and cell migration, and colocalize to dynamic signaling structures. Moreover, retention of WASP together with SCAR correctly predicts α-motility in disease-causing chytrid fungi, which we show crawl at >30 μm/min with actin-filled pseudopods. By focusing on one migration mode in many eukaryotes, we identify a genetic marker of pseudopod formation, the morphological feature of α-motility, providing evidence for a widely distributed mode of cell crawling with a single evolutionary origin.

A codon change in beta-tubulin which drastically affects microtubule structure in Drosophila melanogaster fails to produce a significant phenotype in Saccharomyces cerevisiae

1991 ◽  
Vol 11 (9) ◽  
pp. 4726-4731
Author(s):  
V Praitis ◽  
W S Katz ◽  
F Solomon
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drosophila Melanogaster ◽  
Eukaryotic Cells ◽  
Tubulin Gene ◽  
Beta Tubulin ◽  
Cell Biol ◽  
Codon Change ◽  
Almost All ◽  
Beta Tubulin Gene ◽  
Microtubule Structure

The relative uniformity of microtubule ultrastructure in almost all eukaryotic cells is thought to be a consequence of the conserved elements of tubulin sequence. In support of this idea, a mutation in a beta-tubulin gene of Drosophila melanogaster, occurring at a highly conserved position, produces U-shaped microtubules, suggesting a defect in either nucleation or packing during assembly (M. T. Fuller, J. H. Caulton, J. A. Hutchens, T. C. Kaufman, and E. C. Raff, J. Cell Biol. 104:385-394, 1987, and J. E. Rudolph, M. Kimble, H. D. Hoyle, M. A. Subler, and E. C. Raff, Mol. Cell. Biol. 7:2231-2242, 1987). Surprisingly, we find that introducing the same mutation into the sole beta-tubulin gene of Saccharomyces cerevisiae has virtually no consequences for microtubule structure or function in that organism.

scholarly journals The where and when of intracellular Ca2+ signaling

2019 ◽  
Vol 41 (4) ◽  
pp. 28-31
Author(s):  
Holly Smith
Keyword(s):  
Synaptic Transmission ◽  
Eukaryotic Cells ◽  
Cellular Functions ◽  
Egg Development ◽  
Intracellular Signal ◽  
Almost All

Ca2+ is essential for cellular functions. The ability of this ion to act as an intracellular signal, common to almost all eukaryotic cells, allows it to orchestrate an enormous repertoire of cellular activities, from initiating egg development after fertilization to synaptic transmission between neurons.

scholarly journals Nucleotide dependent differences between the α-skeletal and α-cardiac actin isoforms

2008 ◽  
Vol 368 (3) ◽  
pp. 696-702 ◽  
Author(s):  
József Orbán ◽  
Dénes Lőrinczy ◽  
Miklós Nyitrai ◽  
Gábor Hild
Keyword(s):  
Actin Isoforms ◽  
Cardiac Actin
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