Unleashing formins to remodel the actin and microtubule cytoskeletons

Chesarone, Melissa A.; DuPage, Amy Grace; Goode, Bruce L.

doi:10.1038/nrm2816

Cited by 449 publications

(461 citation statements)

References 168 publications

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“…In the cellular context, Rho protein activates and recruits formins to the plasma membrane leaving diaphanous inhibitory domain (DID) of formins associated with the plasma membrane [26] such that FH1 spans between actin filament barbed end and the plasma membrane. In this ''jack'' model, the plasma membrane serves as the cargo.…”

Section: Conformational Elongation Of Fh1 and Formin Motor Behaviormentioning

confidence: 99%

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

et al. 2014

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a b s t r a c tFilopodia are essential for the development of neuronal growth cones, cell polarity and cell migration. Their protrusions are powered by the polymerization of actin filaments linked to the plasma membrane, catalyzed by formin proteins. The acceleration of polymerization depends on the number of profilin-actins binding with the formin-FH1 domain. Biophysical characterization of the disordered formin-FH1 domain remains a challenge. We analyzed the conformational distribution of the diaphanous-related formin mDia1-FH1 bound with one to six profilins. We found a coil-to-elongation transition in the FH1 domain. We propose a cooperative ''jack'' model for the Formin-Homology-1 (FH1) domain of formins stacked by profilin-actins.

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Section: Conformational Elongation Of Fh1 and Formin Motor Behaviormentioning

confidence: 99%

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

et al. 2014

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“…One of the ways in which actin polymerization is regulated is via formins, which enhance filament formation. Formins contain two conserved domains: Formin homology domain 1 (FH1) binds profilin, and formin homology domain 2 (FH2) binds actin (reviewed in 15,16). A TIRF polymerization experiment was performed in the presence of the constitutively active FH1-FH2 fragment of mouse diaphanous 1 (mDia1).…”

Section: R258 E197 K115mentioning

confidence: 99%

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

Fagnant

Bookwalter

et al. 2015

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

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Point mutations in vascular smooth muscle α-actin (SM α-actin), encoded by the gene ACTA2, are the most prevalent cause of familial thoracic aortic aneurysms and dissections (TAAD). Here, we provide the first molecular characterization, to our knowledge, of the effect of the R258C mutation in SM α-actin, expressed with the baculovirus system. Smooth muscles are unique in that force generation requires both interaction of stable actin filaments with myosin and polymerization of actin in the subcortical region. Both aspects of R258C function therefore need investigation. Total internal reflection fluorescence (TIRF) microscopy was used to quantify the growth of single actin filaments as a function of time. R258C filaments are less stable than WT and more susceptible to severing by cofilin. Smooth muscle tropomyosin offers little protection from cofilin cleavage, unlike its effect on WT actin. Unexpectedly, profilin binds tighter to the R258C monomer, which will increase the pool of globular actin (G-actin). In an in vitro motility assay, smooth muscle myosin moves R258C filaments more slowly than WT, and the slowing is exacerbated by smooth muscle tropomyosin. Under loaded conditions, small ensembles of myosin are unable to produce force on R258C actin-tropomyosin filaments, suggesting that tropomyosin occupies an inhibitory position on actin. Many of the observed defects cannot be explained by a direct interaction with the mutated residue, and thus the mutation allosterically affects multiple regions of the monomer. Our results align with the hypothesis that defective contractile function contributes to the pathogenesis of TAAD.actin | myosin II | smooth muscle | thoracic aortic aneurysms | vascular disease T horacic aortic aneurysms and dissections (TAAD) are the 18th most common cause of death in individuals in the United States (1). The high degree of mortality is partly due to the fact that aneurysms tend to be asymptomatic until a lifethreatening acute aortic dissection occurs. Familial TAAD is an autosomal dominant disorder with variable penetrance, which is characterized by enlargement or dissection of the thoracic aorta (reviewed in 2). The most prevalent genetic cause of familial TAAD, responsible for ∼15% of all cases, are mutations in vascular smooth muscle α-actin (SM α-actin), encoded by the gene ACTA2. More than 40 mutations in ACTA2 have been identified to date (3-5). Intriguingly, ACTA2 mutations also differentially predispose individuals to occlusive vascular diseases, such as premature coronary artery disease and strokes (6). ACTA2 mutations thus can lead to either dilation of large elastic arteries like the aorta or occlusion of smaller muscular arteries.SM α-actin is the most abundant protein in vascular smooth muscle cells, constituting ∼40% of the total protein and ∼70% of the total actin, with the rest composed of β-and γ-cytoplasmic actin. Actin is critical for contraction and force production by smooth muscle cells, as well as for their proliferation and migration. Dissected aortas show s...

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“…As an independent actin nucleator, JMY is part of a group of nucleators that recruit G-actin monomers via tandem repeats of WH2 domains, and the group includes the Spire, cordon-blue and the muscle-specific leiomodin families, the precise actin nucleation mechanism of which is still a matter of debate [8]. Finally, the formin group of nuclea-tors mediates actin polymerization by their signature formin homology (FH)2 domain, which, facilitated by the recruitment of profilin-actin by the adjacent FH1 domain, elongates F-actin filaments from the barbed end via a stair-step mechanism that critically depends on the dimerization of the FH2 domain [9,10]. In addition to these domains, that mediate actin polymerization, the socalled diaphanous formins are subject to autoinhibition [11] mediated by interaction of their C-terminal diaphanous autoregulatory domain (DAD) with an N-terminal region also referred to as diaphanous inhibitory domain (DID) that is part of the FH3 module.…”

Section: Introductionmentioning

confidence: 99%

Differing and isoform-specific roles for the formin DIAPH3 in plasma membrane blebbing and filopodia formation

et al. 2011

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Plasma membrane (PM) blebs are dynamic actin-rich cell protrusions that occur, e.g., during cytokinesis, amoeboid cell motility and cell attachment. Using a targeted siRNA screen against 21 actin nucleation factors, we identify a novel and essential role of the human diaphanous formin DIAPH3 in PM blebbing during cell adhesion. Suppression of DIAPH3 inhibited blebbing to promote rapid cell spreading involving β1-integrin. Multiple isoforms of DIAPH3 were detected on the mRNA and protein level of which isoforms 3 and 7 were the largest and most abundant isoforms that however did not induce formation of actin-rich protrusions. Rather, PM blebbing specifically involved the low abundance isoform 1 of DIAPH3 and activation of isoform 7 by deletion of the diaphanous-autoregulatory domain caused the formation of filopodia. Dimerization and actin assembly activity were essential for induction of specific cell protrusions by DIAPH3 isoforms 1 and 7. Our data suggest that the N-terminal region comprising the GTPasebinding domain determined the subcellular localization of the formin as well as its protrusion activity between blebs and filopodia. We propose that isoform-selective actin assembly by DIAPH3 exerts specific and differentially regulated functions during cell adhesion and motility.

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Unleashing formins to remodel the actin and microtubule cytoskeletons

Cited by 449 publications

References 168 publications

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

Differing and isoform-specific roles for the formin DIAPH3 in plasma membrane blebbing and filopodia formation

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