Mammalian Actins: Isoform-Specific Functions and Diseases

Ampè, Christophe; Troys, Marleen Van

doi:10.1007/164_2016_43

Cited by 27 publications

(37 citation statements)

References 169 publications

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“…Clinically, spontaneous missense mutations in both ACTB and ACTG1 have been associated with Baraitser-Winter syndrome, a rare disease with complex phenotypes, including facial dysmorphism, learning disabilities, and deafness (24). Some of the mutations affect the polymerization properties of actin or interaction with actin binding proteins to cause a gain-of-function or a dominant-negative effect (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Essential nucleotide- and protein-dependent functions ofActb/β-actin

Patrinostro

Roy

Lindsay

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The highly similar cytoplasmic β- and γ-actins differ by only four functionally similar amino acids, yet previous in vitro and in vivo data suggest that they support unique functions due to striking phenotypic differences between and null mouse and cell models. To determine whether the four amino acid variances were responsible for the functional differences between cytoplasmic actins, we gene edited the endogenous mouse locus to translate γ-actin protein. The resulting mice and primary embryonic fibroblasts completely lacked β-actin protein, but were viable and did not present with the most overt and severe cell and organismal phenotypes observed with gene knockout. Nonetheless, the edited mice exhibited progressive high-frequency hearing loss and degeneration of actin-based stereocilia as previously reported for hair cell-specific knockout mice. Thus, β-actin protein is not required for general cellular functions, but is necessary to maintain auditory stereocilia.

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Section: Discussionmentioning

confidence: 99%

Essential nucleotide- and protein-dependent functions ofActb/β-actin

Patrinostro

Roy

Lindsay

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Low-molecular-weight isoforms lack sequences encoded by exon 2 and interact only with six actin subunits. Although most Tpm isoforms show a wider tissue distribution ( 2 ), they are frequently referred to according to their dominant localization as striated muscle, smooth muscle, brain, or cytoskeletal isoforms.…”

Section: Introductionmentioning

confidence: 99%

Three mammalian tropomyosin isoforms have different regulatory effects on nonmuscle myosin-2B and filamentous β-actin in vitro

Pathan-Chhatbar¹,

Taft²,

Reindl³

et al. 2018

Journal of Biological Chemistry

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The metazoan actin cytoskeleton supports a wide range of contractile and transport processes. Recent studies have shown how the dynamic association with specific tropomyosin isoforms generates actin filament populations with distinct functional properties. However, critical details of the associated molecular interactions remain unclear. Here, we report the properties of actomyosin–tropomyosin complexes containing filamentous β-actin, nonmuscle myosin-2B (NM-2B) constructs, and either tropomyosin isoform Tpm1.8cy (b.–.b.d), Tpm1.12br (b.–.b.c), or Tpm3.1cy (b.–.a.d). Our results show the extent to which the association of filamentous β-actin with these different tropomyosin cofilaments affects the actin-mediated activation of NM-2B and the release of the ATP hydrolysis products ADP and phosphate from the active site. Phosphate release gates a transition from weak to strong F-actin–binding states. The release of ADP has the opposite effect. These changes in dominant rate-limiting steps have a direct effect on the duty ratio, the fraction of time that NM-2B spends in strongly F-actin–bound states during ATP turnover. The duty ratio is increased ∼3-fold in the presence of Tpm1.12 and 5-fold for both Tpm1.8 and Tpm3.1. The presence of Tpm1.12 extends the time required per ATP hydrolysis cycle 3.7-fold, whereas it is shortened by 27 and 63% in the presence of Tpm1.8 and Tpm3.1, respectively. The resulting Tpm isoform–specific changes in the frequency, duration, and efficiency of actomyosin interactions establish a molecular basis for the ability of these complexes to support cellular processes with widely divergent demands in regard to force production, capacity to move processively, and speed of movement.

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“…Along with microtubules and intermediate filaments, actin is a major component of the cytoskeleton that defines global and local cellular architecture. Decades of research on the actin cytoskeleton has revealed a plethora of essential roles of actin in cell migration, cell adhesion, mitochondrial dynamics, muscle contraction, protein trafficking, cell division, membrane organization, mechanotransduction and tension sensing, nuclear matrix association, chromatin remodeling and regulation of transcription (Ampe and Van Troys, 2017;Bruser and Bogdan, 2017;Galkin et al, 2012;Lehtimaki et al, 2017;Luxenburg and Geiger, 2017;Pollard, 2017;Sanger et al, 2017;Sheterline et al, 1998;Viita and Vartiainen, 2017).…”

Section: Binding To Actin-associated Proteinsmentioning

confidence: 99%

“…Actin is one of the most abundant intracellular proteins that is present in every eukaryotic cell and plays key roles in many essential biological processes (Box 1). In vertebrates, the six actin isoforms (Table 1) are nearly identical in their amino acid sequences, which are also conserved between species, and yet they are encoded by a set of different evolutionarily conserved genes (see Ampe and Van Troys, 2017;Simiczyjew et al, 2017 for reviews). Despite this high similarity, knockout studies demonstrate that the different actins have distinct biological roles (Perrin and Ervasti, 2010;Wagner et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…This Review summarizes data on the functional regulation of different actin isoforms and the mechanisms that lead to their different biological roles in vivo. We place a special focus on βand γ-non-muscle actins, which are the most similar in amino acid sequence and are both ubiquitously present in all cell types, but play vastly different biological roles (Ampe and Van Troys, 2017;Perrin and Ervasti, 2010;Simiczyjew et al, 2017; see also Box 1). We specifically emphasize recent data highlighting the essential role of the nucleotide sequence in actin function and introduce a new conceptthe 'actin code'that reflects regulation of the essential functions of βand γ-actin at the nucleotide level, a mechanism that is potentially broadly applicable to other members of the actin family.…”

Section: Introductionmentioning

confidence: 99%

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The makings of the ‘actin code': regulation of actin's biological function at the amino acid and nucleotide level

Vedula

Kashina

2018

Journal of Cell Science

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The actin cytoskeleton plays key roles in every eukaryotic cell and is essential for cell adhesion, migration, mechanosensing, and contractility in muscle and non-muscle tissues. In higher vertebrates, from birds through to mammals, actin is represented by a family of six conserved genes. Although these genes have evolved independently for more than 100 million years, they encode proteins with ≥94% sequence identity, which are differentially expressed in different tissues, and tightly regulated throughout embryogenesis and adulthood. It has been previously suggested that the existence of such similar actin genes is a fail-safe mechanism to preserve the essential function of actin through redundancy. However, knockout studies in mice and other organisms demonstrate that the different actins have distinct biological roles. The mechanisms maintaining this distinction have been debated in the literature for decades. This Review summarizes data on the functional regulation of different actin isoforms, and the mechanisms that lead to their different biological roles We focus here on recent studies demonstrating that at least some actin functions are regulated beyond the amino acid level at the level of the actin nucleotide sequence.

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Mammalian Actins: Isoform-Specific Functions and Diseases

Cited by 27 publications

References 169 publications

Essential nucleotide- and protein-dependent functions ofActb/β-actin

Essential nucleotide- and protein-dependent functions ofActb/β-actin

Three mammalian tropomyosin isoforms have different regulatory effects on nonmuscle myosin-2B and filamentous β-actin in vitro

The makings of the ‘actin code': regulation of actin's biological function at the amino acid and nucleotide level

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